This systematic review summarises association between short interpregnancy intervals and adverse perinatal health outcomes in high-resource settings to inform recommendations for healthy birth spacing for the United States. Nine good-quality and 18 fair-quality studies were identified. Interpregnancy intervals <6 months were associated with a clinically and statistically significant increased risk of adverse outcomes in studies of preterm birth (eg, aOR ≥ 1.20 in 10 of 14 studies); spontaneous preterm birth (eg, aOR ≥ 1.20 in one of two studies); small-for-gestational age (eg, aOR ≥ 1.20 in 5 of 11 studies); and infant mortality (eg, aOR ≥ 1.20 in four of four studies), while four studies of perinatal death showed no association. Additional research controlling for confounding would further inform recommendations for healthy birth spacing for the United States. Read More

β-Blockers are a class of antihypertensive medications that are commonly used in pregnancy. The authors aimed to estimate the risks for major congenital malformations associated with first-trimester exposure to β-blockers. Of 3577 women with hypertensive pregnancies in the Nordic cohort and 14 900 in the U.S. cohort, 682 (19.1%) and 1668 (11.2%), respectively, were exposed to β-blockers in the first trimester. The pooled adjusted relative risk and risk difference per 1000 persons exposed associated with β-blockers were 1.07 (95% CI, 0.89 to 1.30) and 3.0 (CI, -6.6 to 12.6), respectively, for any major malformation; 1.12 (CI, 0.83 to 1.51) and 2.1 (CI, -4.3 to 8.4) for any cardiac malformation; and 1.97 (CI, 0.74 to 5.25) and 1.0 (CI, -0.9 to 3.0) for cleft lip or palate. The results suggest that maternal use of β-blockers in the first trimester is not associated with a large increase in the risk for overall malformations or cardiac malformations, independent of measured confounders. Read More

The authors aimed to examine the association of prenatal phthalate exposure with language development in children. Data for this study were obtained from the Swedish Environmental Longitudinal Mother and Child, Asthma and Allergy (SELMA) study and The Infant Development and the Environment Study (TIDES). In adjusted analyses, a doubling of prenatal exposure of dibutyl phthalate and butyl benzyl phthalate metabolites increased the odds ratio (OR) for language delay by approximately 25% to 40%, with statistically significant results in the SELMA study (dibutyl phthalate OR, 1.29 [95% CI, 1.03-1.63; P = .03]; butyl benzyl phthalate OR, 1.26 [95% CI, 1.07-1.49; P = .003]). A doubling of prenatal monoethyl phthalate exposure was associated with an approximately 15% increase in the OR for language delay in the SELMA study (OR, 1.14; 95% CI, 1.00-1.31; P = .05), but no such association was found in TIDES (OR, 0.98; 95% CI, 0.79-1.23). Read More

The authors aimed to describe the characteristics, treatment, and outcomes of pregnant women with opioid use disorder. Out of 113 women enrolled, regular substance used included heroin (92.0%), injection heroin (83.2%), other opioids (69.0%), marijuana (73.5%), alcohol (56.6%), and cocaine (62.8%). Fifty-nine women (52.2%) were treated initially with prenatal buprenorphine and 54 (47.8%) with methadone; 49.6% also were taking concomitant psychotropic medications. Opioid use relapse did not differ by treatment (44.7% overall). Thirteen (22.5%) of 59 women treated with buprenorphine transitioned to methadone mainly because of positive opioid screens. The number of pregnancy losses was small (three therapeutic abortions, four miscarriages, one stillbirth), with an overall live birth rate of 90.8% (95% CI 82.7-95.9). Read More

The authors aimed to use this information to improve the detection of potential teratogens in congenital anomalies (CA) surveillance data. Data on 15,058 malformed foetuses with first trimester medication exposures from 1995-2011 were available from EUROmediCAT. For each medication-CA combination, the proportion of the CA in foetuses with the medication was compared to the proportion of the CA in all other foetuses in the dataset. The Australian classification system was used to identify "high risk" medications in order to compare two methods of controlling the false discovery rate (FDR): a "single" FDR applied across all combinations, and a "double" FDR incorporating groupings of medications. An FDR cut-off of 50% resulted in a reasonable effective workload, for which single FDR gave rise to 8 medication signals (3 "high risk" medications) and double FDR 50% identified 16 signals (6 "high risk"). Read More

Pharmacoepidemiol Drug Saf. 2018 Oct 31. doi: 10.1002/pds.4689.The objective of this study was to describe pregnancy outcomes of women exposed to cancer chemotherapy, recorded in the French Terappel database. In total, 75 questions about "anti-cancer drugs and pregnancy" received were recorded in Terappel. Breast cancer accounted for 62.7% of the cases, followed by leukaemia (13.3%) and lymphoma (9.3%). Cyclophosphamide is the leading anti-cancer drug with 40.0% of exposed pregnant women, followed by 5-fluorouracil (34.7%), epirubicin (32.0%), tamoxifen (26.7%), and doxorubicin (16.0%). Among the 75 pregnancies, we observed 55 births with 57 children (73.3%), nine medical terminations of pregnancy (12.0%), six voluntary terminations of pregnancy (8.0%), three intrauterine foetal deaths (4.0%), and two miscarriages (2.7%). The authors found a malformation rate of 7.8%. Sixteen of 57 (28.1%) newborns developed one or more neonatal pathologies. Read More

The 2003 revision of the US Standard Certificate of Live Birth (birth certificate) and Pregnancy Risk Assessment Monitoring System (PRAMS) are important for maternal weight research and surveillance. The authors examined quality of pre-pregnancy body mass index (BMI), gestational weight gain, and component variables from these sources. For most maternal weight variables, mean differences between the birth certificate or PRAMS compared to the medical record were less than 1 kg. Compared to the medical record, the birth certificate classified similar proportions into pre-pregnancy BMI categories (agreement=89%, κ=0.83); PRAMS slightly underestimated overweight and obesity (agreement=84%, κ=0.73). Read More

The purpose of this study was to examine the independent and joint contributions of familial severe mental illness and obstetric complications to the risk of intellectual disability. For children of mothers with schizophrenia, the unadjusted odds ratio was 3.8 (95% CI=3.0, 4.9) and remained significant after simultaneous adjustment for exposure to obstetric complications and other covariates (odds ratio=1.7, 95% CI=1.3, 2.3). The odds ratio for exposure to obstetric complications also remained significant after adjustment (odds ratio=1.7, 95% CI=1.6, 1.8). For intellectual disability of a genetic basis, the adjusted odds ratio for maternal schizophrenia was elevated but not statistically significant. Read More

The authors systematically reviewed literature on the association between maternal or neonatal thyroid hormones and ADHD diagnosis or symptoms. The authors identified 28 eligible articles: 16 studies of maternal thyroid hormones, seven studies of early-treated congenital hypothyroidism, and five studies of neonatal thyroid hormones. The studies provide moderate evidence for an association between maternal thyroid hormone levels and offspring ADHD, some evidence for an association between early-treated congenital hypothyroidism and ADHD, and little evidence for an association between neonatal thyroid hormone levels and later ADHD. Read More

Oseltamivir in pregnancy and birth outcomes.Ehrenstein V, Kristensen NR, Monz BU, Clinch B, Kenwright A, Sørensen HT.BMC Infect Dis. 2018 Oct 16;18:519. doi: 10.1186/s12879-018-3423-z.The authors examined the association between oseltamivir use during pregnancy and birth outcomes. The study included 946,176 pregnancies. Of these, 449 had first-trimester exposure and 1449 had second/third-trimester exposure to oseltamivir. Adjusted ORs following first-trimester exposure were 0.94 (95% CI 0.49 to 1.83) for any major congenital malformation and 1.75 (95% CI 0.51 to 5.98) for congenital heart defects, based on 7 exposed cases. The association with congenital heart defects was present for etiologically implausible exposure periods and for known safe exposures. There was no evidence of an association between prenatal exposure to oseltamivir and any of the other birth outcomes assessed. Read More

The objective of this study was to perform a systematic review of the safety of inactivated influenza vaccination (IIV) in pregnancy. Crude odds ratios were calculated from reported event rates, using binomial standard errors. Adjusted odds ratios, hazard ratios and relative rates were extracted as reported in each paper. After removal of duplicates and full text eligibility assessment, 40 studies remained. The aOR for PTB was 0.87 (0.78-0.96), for LBW 0.82 (0.76-0.89), congenital abnormality 1.03 (0.99-1.07), SGA 0.99 (0.94-1.04) and stillbirth 0.84 (0.65-1.08). This study contributes to the increasing body of safety data for IIV in pregnancy and reports a protective effect on PTB and LBW. Read More

The objective of this study was to assess the feasibility of using social media data as an alternative source for pregnancy surveillance for regulatory decision making. The authors created an automated method to identify Twitter accounts of pregnant women. The authors identified 196 pregnant women with a mention of a birth defect in relation to their baby and 196 without a mention of a birth defect in relation to their baby. After accounting for age, race, and place of residence, a higher medication intake was observed in women who reported birth defects. Development of improved methods to automatically extract and annotate social media data may increase their value to support regulatory decision making regarding pregnancy outcomes in women using medications during their pregnancies. Read More

The objective of this study was to assess the frequency of maternal HepB receipt among pregnant women and evaluate the potential association between maternal vaccination and pre-specified maternal and infant safety outcomes. The authors compared pregnancies with HepB exposure to those with other vaccine exposures, and to those with no vaccine exposures. Less than 3% of the HepB-exposed group had a high-risk ICD-9 code indicating need for HepB; this was similar to the rate among HepB unvaccinated groups. There were no significant associations between HepB exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, low birthweight or small for gestational age infants. Read More

The aim of this study was to assess the association between maternal use of hormonal contraception and diagnosis of leukaemia in their children. Children born to women with recent use of any type of hormonal contraception were at higher risk for any leukaemia than children of women who never used contraception (HR 1·46, 95% CI 1·09-1·96; p=0·011); and for exposure during pregnancy the risk was 1·78 (0·95-3·31; p=0·070). No association was found between timing of use and risk for lymphoid leukaemia (HR 1·23, 95% CI 0·97-1·57, p=0·089, for previous use and 1·27, 0·90-1·80, p=0·167, for recent use); however, the HRs for non-lymphoid leukaemia were 2·17 (1·22-3·87; p=0·008) for recent use and 3·87 (1·48-10·15; p=0·006) for use during pregnancy. Hormonal contraception use close to or during pregnancy might have resulted in one additional case of leukaemia per about 50 000 exposed children, or 25 cases during the 9-year study period. Read More

The authors examined the association between early exposure to antibiotics and childhood type 1 diabetes. The authors excluded (n=4,828) twins and triplets, children born before gestational week 26 children weighing, 500g at birth, and stillbirths. Socioeconomic status, parity, maternal diabetes, smoking during pregnancy, or cesarean section were unknown in 16,383 individuals, leaving 75,629 for adjusted analyses. The children were followed until 2014 (mean follow-up time 14.3 years [range 11.5–18.4 years, SD 1.4]). This large prospective Danish cohort study demonstrated that maternal use of antibiotics during pregnancy was not associated with childhood type 1 diabetes. Read More

Surveillance of drug safety during pregnancy: insight in current international activities, future intentions and need for support of national pharmacovigilance centres.Kant A, de Vries L, Rolfes L.Drug Saf. 2018 Oct 3. doi: 10.1007/s40264-018-0729-0.

The aim of this study was to provide insight into current activities, future intentions and need for support of national PV centres in the field of drug safety during pregnancy.A web-based questionnaire was used to ask PV centres about their current activities concerning the surveillance of drug safety during pregnancy, their intentions to implement or improve activities and need for support. The questionnaire was sent to PV centres of 172 countries. Response was 40%. In general, the PV centres received limited numbers of reports of ADRs in the (unborn) child, related to drug exposure during pregnancy. Signal detection in pregnancy cases is carried out by 8 out of 58 PV centres (13.5%). Most PV centres mention they have intentions to implement or improve activities, mainly for spontaneous reporting (69.4%) and methods for signal detection (67.2%). Support was needed for all topics of the questionnaire. Read More

The authors studied mild influenza and influenza antibodies in relation to birth weight and risks of pre-eclampsia, preterm birth (PTB), and small for gestational age (SGA) birth among the unvaccinated participants in the Norwegian Influenza Pregnancy Cohort. Among the 1258 women included in this study, there were 37 cases of pre-eclampsia, 41 births were PTB, and 103 births were SGA. 226 women (18.0%) had influenza during the pandemic. The majority of cases did not receive medical care, and only a small proportion (1.3%) of the cases were hospitalized. Thus, the cases consisted primarily of women with mild illness. No significant associations between influenza and risk of pre-eclampsia, PTB, or SGA birth were observed. Detection of A(H1N1)pdm09-specific antibodies was associated with a lower 10th percentile of birth weight, β = - 159 g (95% CI - 309, - 9). Read More

This systematic review summarises the evidence of follow-up studies of randomised controlled trials (RCTs) reporting on long-term effects of prenatal exposure to OADs on offspring. Ten studies were included, with a maximal follow-up duration of 9 years, comprising 778 children of mothers with GDM or PCOS who were randomised to either metformin or insulin/placebo during pregnancy. Meta-analysis showed that children prenatally exposed to metformin were heavier compared to controls (standardized mean difference (SMD) 0.26 [95% CI 0.11-0.41]), but not taller (SMD 0.10 [95% CI -0.14-0.33]). Additionally, offspring body mass index (BMI) z scores did not differ according to metformin exposure (mean difference 0.30 [95% CI -0.01-0.61]). Read More

This study sought to describe (1) the characteristics of adolescents aged 11-17 who experienced opioid-related non-fatal overdose (NFOD) and (2) their receipt of medications for opioid use disorder (MOUD) in the 12 months following NFOD, compared with adults. Authors created a retrospective cohort using six Massachusetts state agency datasets linked at the individual level to identify patients who experienced NFOD between 2012-2014. Among all individuals who experienced NFOD, 0.9% were aged 11-17. Fifty-two percent of adolescents were female, whereas only 38% of adults were female (p < 0.001). In the year prior to NFOD, 11% of adolescents received a prescription opioid, compared to 43% of adults (p < 0.001). Few adolescents received MOUD before or after NFOD. Read More

This study assessed the current state of the art in pediatric comparative effectiveness research, potential gaps, and areas for improvement. Relevant articles from inception to February 2015 were retrieved from Embase and Medline, and study quality was assessed using Newcastle-Ottawa Scale (NOS). Sixty four articles were included in the review; most studies were from North America (46.7%). Only 78 studies (47.6%) reported the design: 90.8% were cohort studies. The drugs that were most often studied included systemic antibacterials (11.4%), psycholeptics (7.9%), and antiepileptics (7.6%). Adjustment for confounding was made using propensity scores in 8.5% of the studies. There is ample opportunity to improve comparative effectiveness research for drugs used in pediatrics. Read More

To examine the associations between atypical antipsychotic (AAP) exposure and the development of type 2 diabetes mellitus (T2DM) in Korean pediatric patients (2-19 years) with psychiatric disorders, the authors conducted a nested case-control study using the claims data of the National Health Insurance system of Korea between 2010 and 2014. Conditional logistic regression was used to assess associations between AAP exposure and T2DM. The authors identified 20,263 cases with T2DM and 80,043 controls, matched by sex, age, enrollment date, and primary psychiatric diagnosis. After adjusting for potential confounders, the odds of having T2DM was significantly higher in multi-AAP users compared with non-users (OR 1.89; 95% CI 1.63-2.20). The association was particularly high when comparing clozapine users vs. non-users (OR 3.47; 95% CI 1.88-6.41). These findings suggest a significantly increased risk of developing T2DM in child or adolescent patients with psychiatric disorders exposed to AAPs compared with those not exposed to AAPs. Read More

The authors conducted a scoping review to examine the concept of pediatric polypharmacy: its definition, prevalence, extent and gaps in research. In this manuscript, they report their transdisciplinary scoping review methodology. The transdisciplinary team of nine members performed dual reviews of 363 included studies after dual screening of 4398 abstracts and 1082 full text articles. The team achieved overall agreement of 85% and a kappa coefficient of 0.71 (95% CI 0.68-0.74) while screening full text articles. Read More

The aim of this study was to identify subgroups of women who exhibit distinct trajectory patterns of depressive and anxiety disorders from pregnancy to early postpartum and the risk factors associated with the latent trajectory group memberships. The authors identified four latent trajectory groups of perinatal depressive symptoms: "low-stable" (49.6%), "moderate-stable" (42.3%), "postpartum" (3.6%), and "antepartum" (4.6%). Significant risk factors associated with these trajectory group memberships were past depression, stress level, ethnicity, the mother's age, and relationship satisfaction. Read More

Maternal thyroid dysfunction may adversely affect fetal brain development, but more evidence is needed to refine this hypothesis. The aim of this study was to evaluate potential fetal programming by abnormal maternal thyroid function on child neurodevelopmental disorders. The design was a case-cohort study within the Danish National Birth Cohort (1997-2003). The authors concluded that abnormal maternal thyroid function in early pregnancy was associated with epilepsy, ASD, and ADHD in the child, but associations differed by subtypes of exposure and by child age and sex. More evidence on subtypes and severity of maternal thyroid function is needed, and alternative outcomes of child neurodevelopment may be warranted. Read More

The objective of this study was to investigate whether first-trimester use of beta-blockers increases the risk of specific congenital anomalies in offspring. A population-based case-malformed control study was conducted in 117,122 registrations of congenital anomalies from 17 European Concerted Action on Congenital Anomalies and Twins (EUROCAT) registries... The authors concluded that Beta-blocker use in the first trimester of pregnancy was not found to be associated with a higher risk of specific congenital anomalies in the offspring, but a new signal between alpha- and beta-blockers and multi-cystic renal dysplasia was found. Read More

The authors aimed to quantify the risk of major congenital malformation (MCM), prematurity, low birth weight (LBW) and spontaneous abortion associated with leflunomide exposure during pregnancy in humans. From a cohort of 289 688 pregnancies in Canada, from 1998 to 2015, 51 pregnancies were exposed to leflunomide during the first trimester, and 21 during the second/third trimesters. The authors concluded that maternal exposure to leflunomide during pregnancy was not associated with statistically significant increased risk of MCMs, prematurity, LBW or spontaneous abortions. However, given that relatively few women were exposed to leflunomide during pregnancy in this cohort, caution remains warranted. Read More

Pregnancy outcomes after exposure to certolizumab pegol: updated results from a pharmacovigilance safety database.Clowse MEB, Scheuerle AE, Chambers C, Afzali A, Kimball AB, Cush JJ, Cooney M, Shaughnessy L, Vanderkelen M, Förger F.Arthritis Rheumatol. 2018 Apr 5. doi: 10.1002/art.40508. [Epub ahead of print]Anti-tumor necrosis factor medications (anti-TNFs) are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti-TNFs are often discontinued early in gestation. This project provides information on pregnancy outcomes in women receiving CZP, especially those with early pregnancy exposure. Out of 1137 maternal CZP-exposed prospective pregnancies, 528 (including 10 twin pregnancies) had 538 known outcomes: 459 live births (85.3%), 47 miscarriages (8.7%), 27 elective abortions (5.0%), and 5 stillbirths (0.9%). There were 8 major congenital malformations (1.7%) among the 459 infants. Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP, compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with CZP. Read More

There is increasing interest in the possible link between maternal hypothyroidism in the perinatal period and childhood asthma risk. The authors explored this in this study while accounting for the timing of hypothyroidism diagnosis. Further, they evaluated whether the risk was moderated by thyroid hormone treatment during pregnancy. A population-based cohort study was conducted using Danish national registers. The authors concluded that the findings suggest maternal hypothyroidism, especially when it is untreated, increases childhood asthma risk. Early detection and appropriate treatment of hypothyroidism in pregnant women may be an area for possible prevention of childhood asthma. Read More

Acetaminophen is the most commonly used analgesic and antipyretic during pregnancy. Evidence of neuro-disruptive properties is accumulating. The authors sought to evaluate the risk for attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorder (ASD) in the offspring of women exposed to acetaminophen during pregnancy. We searched MEDLINE, EMBASE, and Cochrane up to January 2017. Seven eligible retrospective cohorts included 132,738 mother and child pairs and with a follow-up period of 3-11 years. Pooled risk ratio (RR) for ADHD was (RR=1.32, 95% CI 1.18,1.45, I2=61%), for ASD (RR=1.23, 95% CI1.13,1.32, I2=17%), and for hyperactivity symptoms (RR=1.23, 95% CI 1.01,1.49, I2=94%). Studies differed gravely in exposure and outcome assessment. Read More

Prediction models may contribute to personalized risk-based management of women at high risk of spontaneous preterm delivery. The authors performed a systematic review of prediction models for the risk of spontaneous preterm birth based on routine clinical parameters. Additionally, they externally validated and evaluated the clinical potential of the models. Risk of bias assessment revealed a moderate to high risk of bias in three out of four studies that fulfilled the eligibility criteria. The AUC of the models ranged from 0.54 to 0.67 and from 0.56 to 0.70 for the outcomes spontaneous preterm birth <37 weeks and <34 weeks of gestation, respectively. This external validation study indicated that none of the models had the ability to predict spontaneous preterm birth adequately in the testing population. Read More

Antibiotics during pregnancy alter the microbiome and may influence disease risks in the offspring. The authors investigated the relationship between maternal antibiotic exposure before and during pregnancy, and risk of childhood hospitalization with infection. Pregnancy antibiotic exposure was associated with increased risk of childhood infection-related hospitalization [HR 1.18, 95% CI 1.17-1.19]…The authors concluded that antibiotic exposure before or during pregnancy was associated with increased risk of childhood hospitalized infections. Alteration of the maternally derived microbiome and shared heritable and environmental determinants are possible contributory mechanisms. Read More

For hypertensive women in Control of Hypertension in Pregnancy Study, the authors assessed whether the maternal benefits of tight control could be achieved, while minimizing any potentially negative effect on fetal growth, by delaying initiation of antihypertensive therapy until later in pregnancy. For the 981 women with nonsevere, chronic or gestational hypertension randomized to less-tight (target diastolic blood pressure, 100 mm Hg), or tight (target, 85 mm Hg) control, they used mixed-effects logistic regression to examine whether the effect of less-tight control on major outcomes was dependent on gestational age at randomization. In summary, this secondary exploratory analysis of CHIPS data has shown that there is no gestational age at which less tight control is the preferred clinical option, for women with chronic or gestational hypertension.Read More

The influence of prenatal mental health service use on the incidence of childhood asthma: a population-based cohort study.Radhakrishnan D, Shariff SZ, To T.J Asthma. 2018 Apr 25:1-35. doi: 10.1080/02770903.2018.1466313. [Epub ahead of print]

The authors aimed to determine whether maternal mental health service use during pregnancy, a potential proxy measure of prenatal maternal stress, is associated with the development of asthma in a large population-based sample of children. They hypothesized that children born to mothers with mental health service use during pregnancy would have a higher incidence of childhood asthma. In a population-based sample of 122,333 children, those born to mothers with mental health service use during pregnancy had increased odds of developing asthma (OR: 1.16, 95% CI: 1.12, 1.20 p<0.001). The authors concluded that prenatal maternal mental health service use is an independent risk factor for the development of asthma in childhood. Read More

Maternal anxiety, depression and sleep disorders before and during pregnancy, and preschool ADHD symptoms in the NINFEA birth cohort study.Vizzini L, Popovic M, Zugna D, Vitiello B, Trevisan M, Pizzi C, Rusconi F, Gagliardi L, Merletti F, Richiardi L.Epidemiol Psychiatr Sci. 2018 Apr 18:1-11. doi: 10.1017/S2045796018000185. [Epub ahead of print]Maternal mental disorders have been associated with the risk of attention-deficit/hyperactivity disorder (ADHD) in children. In this study, the authors examined whether maternal anxiety, depression and sleep disorders are associated with pre-school ADHD symptoms. The authors found that the total ADHD score at age 4 was associated with maternal lifetime anxiety (17.1% percentage difference in score compared with never; 95% CI 7.3-27.9%), sleep disorders (35.7%; 95% CI 10.7-66.5%) and depression (17.5%; 95% CI 3.2-33.8%). Similar positive associations were observed also for ADHD-H and ADHD-I traits, with slightly attenuated associations between maternal sleep disorders and child ADHD-I score, and maternal depression and both ADHD scores. All the estimates were enhanced when the disorders were active during pregnancy and attenuated for disorders active only during the pre-pregnancy period. Read More

The authors conducted an ecologic register-based study to investigate further the reported adverse events after PCV. Data from Finnish Population Register during 2000-2014 for children age from 3 months to 10 years were used to estimate annual incidence rates. Incidence rate ratios of the outcomes were calculated between the target cohort of children eligible for PCV10 during 2010-2014 and a reference cohort before the NVP introduction (2004-2008). The authors concluded that the results do not support public health concerns related to the previously reported adverse events. They consider this register-based approach with real-world data feasible in the signal validation process after any signal detection. Read More

Use of available clinical evidence to extrapolate drug effects from adults to children.Janiaud P, Glais F, Grenet G, Lajoinie A, Cornu C, Kassai-Koupai B.Therapie. 2018 Apr;73(2):119-125. doi: 10.1016/j.therap.2017.11.007. Epub 2018 Feb 16.Using a meta-epidemiological approach, the authors explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses, as well as the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. This study highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children. Read More

Evaluation of dystonia in children and adolescents treated with atomoxetine within the Truven MarketScan database: a retrospective cohort study.Meyers KJ, Upadhyaya HP, Goodloe R, Kryzhanovskaya LA, Liles-Burden MA, Kellier-Steele NA, Mancini M.Expert Opin Drug Saf. 2018 May;17(5):467-473. doi: 10.1080/14740338.2018.1462333. Epub 2018 Apr 13.In this study, the incidence and risk of dystonia in children and adolescents treated with atomoxetine was compared to a propensity score-matched cohort of stimulant users. The hazard ratio for occurrence of dystonia with atomoxetine use relative to stimulant usewas 0.68 (95% CI: 0.36 - 1.28; P = 0.23). In this large retrospective cohort study, the author concluded that there was no significant difference in incidence or risk of dystonia among patients treated with atomoxetine compared to stimulants…Read More

The present study is a narrative review of the literature of off-label and unlicensed drug use from 2013. The authors performed a literature search of research articles assessing Off-label (OL) and unlicensed (UL) drug use in children (<18 years-old) published in Medline® from January 2013 until May 2017. Among in- and out-patients, the frequency of patients exposed to at least one OL-UL drug ranged from 36.3 to 97.0% and from 18.6 to 40.2%, respectively. The authors concluded that OL-UL drug use is frequent in children. A standardized definition ofOL-UL drug use is needed to better assess its frequency, risk factors and impact. Read More

Pharmacoepidemiology in pediatrics: needs, challenges and future directions for research.Osokogu OU, Verhamme K, Sturkenboom M, Kaguelidou F.Therapie. 2018 Apr; 73(2):151-156. doi: 10.1016/j.therap.2017.11.009. Epub 2018 Feb 21.In this paper, the authors provide an overview of the particular interest of pharmacoepidemiological research into the evaluation of drug effects in children and adolescents...Implementation of innovative methodologies and expansion of database networks to perform necessary studies could further improve performances of observational research. Read More

Effectiveness of influenza vaccination for children in Japan: four-year observational study using a large-scale claims database.Shibata N, Kimura S, Hoshino T, Takeuchi M, Urushihara H.Vaccine. 2018 May 11;36(20):2809-2815. doi: 10.1016/j.vaccine.2018.03.082. Epub 2018 Apr 13.In this study, the authors evaluated the clinical effectiveness of influenza vaccination for children aged 1-15 years in Japan throughout four influenza seasons from 2010 to 2014 in the real-world setting. They conducted a cohort study using a large-scale claims database for employee health care insurance plans covering more than 3 million people, including enrollees and their dependents. The authors concluded that they confirmed the clinical effectiveness of influenza vaccination in children aged 1-15 years from the 2010/2011 to 2013/2014 influenza seasons. Read More

Racial/ethnic differences in the treatment of adolescent major depressive disorders (MDD) across healthcare providers participating in the Medicaid program.Yucel A, Essien EJ, Sanyal S, Mgbere O, Aparasu RR, Bhatara VS, Alonzo JP, Chen H.J Affect Disord. 2018 Aug 11; 235:155-161. doi: 10.1016/j.jad.2018.04.045. [Epub ahead of print]This study aimed to examine whether racial/ethnic differences in receipt of MDD treatment could be explained by the specialty of provider diagnosing the adolescent. Adolescents (10-20 years-old) with ≥2 MDD diagnoses were identified using 2005-2007 Medicaid data from Texas. Patients were categorized based on the types of provider who gave the initial MDD diagnosis (psychiatrist (PSY-I), social worker/psychologist (SWP-I), and primary care physician (PCP-I)). The authors concluded that for adolescents with MDD, being first diagnosed by a psychiatrist was associated with higher treatment rate and reduced racial/ethnic variation in the utilization of pharmacotherapy. Read More

Although congenital abnormalities in the male reproductive tract are common, their causes remain poorly understood. The authors studied associations between hypertensive disorders of pregnancy and the genital anomalies, cryptorchidism, and hypospadias. They found associations between pre-gestational hypertension and cryptorchidism [HR: 1.3 (95% CI: 1.1, 1.6)] and hypospadias [HR: 1.7 (95% CI:1.3, 2.3)], whereas gestational hypertension was only associated with cryptorchidism [HR: 1.2 (95% CI: 1.1, 1.4)]. Boys of mothers with preeclampsia had the highest occurrence of cryptorchidism and hypospadias, increasing with preeclampsia severity. Further, the occurrence increased with early onset of preeclampsia diagnosis.Read More

The objective of this study was to investigate the effect of expanding Medicaid health insurance coverage for unauthorized women on prenatal care utilization. The authors examined the prenatal care utilization of 20,876 unauthorized women from Nebraska, which expanded Medicaid coverage for unauthorized women, and South Carolina, which has never expanded coverage. Analysis entailed a difference-in-difference approach to compare prenatal care utilization by state, both before and after legislation was passed to fund care among unauthorized women in Nebraska. Unauthorized women living in Nebraska during Medicaid expansion were 28% more likely to receive adequate prenatal care (OR=1.28, p<0.01) and had about one more prenatal care visit (IRR=1.05, p<0.01) than women who did not have expanded Medicaid coverage.Read More

The authors conducted a review of publications reporting associations between prenatal APAP use and offspring neurodevelopmental outcomes. Sources were identified through a key word search of multiple databases (Medline, CINAHL, OVID and TOXNET) in September 2016. 64 studies were retrieved and nine prospective cohort studies fulfilled all inclusion criteria. Data pooling was not appropriate due to heterogeneity in outcomes. All included studies suggested an association between prenatal APAP exposure and the neurodevelopmental outcomes; ADHD, ASD, or lower IQ. Longer duration of APAP use was associated with increased risk. Associations were strongest for hyperactivity and attention-related outcomes. Little modification of associations by indication for use was reported.Read More

It is recommended that all pregnant women in the U.S. receive tetanus, diphtheria, acellular pertussis (Tdap) immunization to prevent infant pertussis. This study's objective was to examine the clinical effectiveness of prenatal Tdap, and whether effectiveness varies by gestational age at immunization. There were 675,167 mother-infant pairs in the cohort. Among infants whose mothers received prenatal Tdap, the rate of pertussis was 43% lower (hazard ratio=0.57, 95% CI=0.35, 0.92) than infants whose mothers did not receive prenatal or postpartum Tdap. Pertussis rates were also lower for infants whose mothers received Tdap during the third trimester. Infants whose mothers received Tdap at <27 weeks of gestation did not experience reductions in pertussis rates (hazard ratio for pertussis=1.10, 95% CI=0.54, 2.25).Read More

The authors developed an algorithm to identify pregnancy episodes in the French health care databases and applied it to study antiepileptic drug (AED) use during pregnancy. To differentiate claims associated with separate pregnancies, an interval of at least 28 weeks was required between 2 consecutive pregnancies resulting in a birth and 6 weeks for terminations of pregnancy. According to the algorithm, live birth was the most common pregnancy outcome (73.9%), followed by elective abortion (17.2%), spontaneous abortion (4.2%), ectopic pregnancy (1.1%), therapeutic abortion (1.0%), and stillbirth (0.4%). Among 7,559,701 pregnancies starting between 2007 and 2014, 6.7 per 1000 pregnancies were exposed to an AED. The number of pregnancies exposed to older AEDs, comprising the most teratogenic AEDs, decreased throughout the study period (-69.4%), while the use of newer AEDs increased (+73.4%). Read More

The aim of this study was to assess the impact of prenatal diagnosis in Portugal in pregnancies with congenital anomalies. At least one malformation was detected for the first time through ultrasound (47.4%), invasive tests (5.6%) and other tests (2.2%). When analysed severe congenital anomalies (CA), 54.2% was detectible by prenatal ultrasound. Terminations of Pregnancies for Foetal Anomaly (TOPFA) was the option for 21.3% of these CA. Over the 20 years of analysis, there was a statistically significant increase trend in the detection rate of congenital anomalies through prenatal diagnosis compared to detection at birth or after birth (p < 0.001). After adjustment for confounders, prenatal diagnosis was associated with more severe outcomes (TOPFA, 40.3%; Death 3.5%) and increased the risk of the pregnancy ending in foetal death (OR = 2.56; 95%CI = 2.06-3.18). Read More

The Authors aimed to quantify the risk of prematurity associated with late pregnancy exposure to nonselective NSAIDs, selective COX-2 inhibitors, and biological agents. Late pregnancy exposure was defined as having filled at least 1 prescription for nonselective NSAIDs, selective COX-2 inhibitors, or biological agents in the 3 months before delivery. After adjustment for maternal autoimmune diseases, concomitant medication use, and other risk factors, COX-2 inhibitor use in late pregnancy was associated with a 2.46-fold increased risk of prematurity (adjusted OR, 2.46; 95% CI, 1.28-4.72) compared to nonuse; only late pregnancy exposure to celecoxib was found to increase the risk (adjusted OR, 3.41; 95% CI, 1.29-9.02).Read More

The association between the use of nimesulide in early pregnancy and the risk of birth defects was investigated in a large cohort of pregnant women from Italy. Exposure to nimesulide during the first trimester of pregnancy, and congenital malformations detected at presentation and within 90 days after birth (outcome), were investigated. Exposure-outcome association was measured by the ratio between the prevalence of congenital malformations among users and non-users of nimesulide. The 627 (0.18%) women who filled prescriptions for nimesulide in the first trimester of pregnancy had a 2.6-fold risk of having children with congenital urinary tract anomalies compared to those who did not (adjusted prevalence ratio 2.6; 95% CI 1.2-5.7). Weaker and non-significant evidence for congenital malformations as a whole was found (adjusted prevalence ratio 1.2, 95% CI 0.9-1.6). Read More

The authors aimed assess whether hypertensive disorders during pregnancy (HDPs) are associated with the subsequent development of end-stage renal disease (ESRD). The present study included 1 598 043 women who delivered in Canadian hospitals between April 1993 and March 2003. An increased risk of ESRD hospitalization was observed in pregnant women with pre-eclampsia/eclampsia (adjusted hazard ratio [aHR] = 4.7, 95% CI 3.6-6.0), unspecified HDPs (aHR = 4.6, 95% CI 2.8-7.7), or gestational hypertension (aHR = 3.3, 95% CI 2.1-5.1). The risk of subsequent ESRD hospitalization appeared to be lower for women who had ≥2 deliveries compared with those who had one delivery during the study period. Read More

The authors aimed to examine the effects of infertility treatments on the risk of Autism Spectrum Disorder (ASD). Data were from a representative national registry on 110,093 male live births in Israel (born: 1999-2008; and ASD: 975, 0.9%). Infertility treatments included In Vitro Fertilization (IVF), and five hormone treatments. Results showed that IVF treatment compared with spontaneous conception was not statistically significantly associated with the risk of ASD. Only progesterone hormone treatment was associated with a statistically significant (p < .05) increased risk of ASD (RR = 1.51, 95% CI 1.22, 1.86) compared to the group with no progesterone treatment. Read More

The authors undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case-control study of the Norwegian Mother and Child Cohort (MoBa). Cases of ADHD (n=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (n=553) from the MoBa population was obtained. In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest [OR=2.99 (95% CI: 1.47, 5.49)]. When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [OR=1.47 (95% CI: 1.09, 1.94)]. Read More

The authors estimated the effect of pregnancy on disease flares in systemic lupus erythematosus. The time-varying exposures were classified as pregnancy, postpartum or non-pregnant/non-postpartum periods. There was an increased rate of flare defined by PGA during pregnancy (HR: 1.59; 95% CI 1.27 to 1.96); however, this effect was modified by hydroxychloroquine (HCQ) use, with the HR of flares in pregnancy compared with non-pregnant/non-postpartum periods estimated to be 1.83 (95% CI 1.34 to 2.45) for patients with no HCQ use and 1.26 (95% CI 0.88 to 1.69) for patients with HCQ use. The risk of flare was similarly elevated among non-HCQ users in the 3 months postpartum, but not for women taking HCQ after delivery. Read More

The goal of this analysis was to examine the effect of benzodiazepine use during pregnancy on maternal and neonatal outcomes in a cohort of women with psychiatric disorders. 794 evaluable women from the Massachusetts General Hospital National Pregnancy Registry for Psychiatric Medications were followed across pregnancy (N = 144 exposed to benzodiazepines and N = 650 unexposed). In adjusted analyses, infants exposed to benzodiazepines in utero were more likely to be admitted to the NICU (OR: 2.02, 95% CI: 1.11, 3.66) and to have small head circumferences (OR: 3.89, 95% CI: 1.25, 12.03) compared to unexposed infants. Other neonatal adverse effects such as respiratory distress or muscular symptoms including hypotonia were not observed. There were no significant differences in adverse obstetrical outcomes. Read More

Previous studies suggest that women with hypertensive disorders of pregnancy (HDP) are at increased risk of subsequent cardiovascular disease (CVD). However, it is unclear whether this association differs by timing of onset of HDP. In this study, they found that compared with women with no HDP, those with early-onset HDP had a higher risk of developing incident CVD (HR 2.6, 95% CI 1.5, 4.3) and hypertension (HR 4.3, 95% CI 3.6, 5.0). Wide CIs precluded any conclusions regarding a difference in the risk of incident CVD and hypertension in women with early- vs late-onset HDP (HR 0.90, 95% CI 0.50, 1.62 and HR 1.06, 95% CI 0.87, 1.28, respectively).Read More

Triptans are commonly used to treat migraine headaches, but data on the long-term safety of these medications during pregnancy are sparse. The authors included 3784 children in the Norwegian Mother and Child Cohort Study, whose reported a history of migraine or triptan use. 353 (9.3%) mothers reported use of triptans during pregnancy, 1509 (39.9%) reported migraine during pregnancy but no triptan use, and 1922 (50.8%) had migraine prior to pregnancy only. Triptan-exposed children scored higher on the sociability trait than unexposed children of mothers with migraine (β 1.66, 95% CI [0.30, 3.02]). Read More

The authors aimed to describe the utilization of drugs with pregnancy exposure registries by trimester during pregnancy, in comparison with matched nonpregnant episodes and a pre-pregnancy period. They observed a lower prevalence of use for most drugs during pregnancy compared with the matched nonpregnant episodes, and the 90-day pre-pregnancy period. The median (interquartile range) prevalence ratio of use, at any time during pregnancy, for all products was 0.2 (0.1-0.3) comparing pregnant to nonpregnant episodes. Overall, there was a decrease in drug utilization by trimester; from 2.6% in the 90 days preceding pregnancy to 2.1% in the first trimester, 1.1% in the second trimester, and 0.9% in the third trimester. Read More

The aim of this study was to systematically review epidemiological evidence on the potential association of prenatal exposure to ondansetron and congenital malformations. Ten epidemiologic studies were included: five large retrospective cohort studies, two prospective observational studies, two population-based case-controls and a retrospective case series. A case-control study identified an association between prenatal exposure to ondansetron and cleft palate, and one cohort study found an increased risk of cardiovascular defects. These findings were not reproduced in the other studies. Read More

Pre-existing conditions are imperfectly recorded in health care databases. The authors assessed whether pre-existing neurologic conditions (epilepsy, multiple sclerosis [MS]) were differentially recorded in the presence of major obstetric outcomes in delivery records. Of women with epilepsy identified in the pre-delivery window, 73% had the condition coded at delivery. For MS, the proportion was 60%. MS recording at delivery did not vary by obstetric outcomes, however, delivery-coded epilepsy was less likely confirmed in the pre-delivery window in the presence of preeclampsia. Generally, the period of ascertainment did not meaningfully impact risk ratios, however, the risk ratio for preeclampsia associated with epilepsy was 1.67 (95% CI 1.47, 1.90) when epilepsy was ascertained at delivery and 1.26 (95% CI 1.07, 1.48) when epilepsy was ascertained in the pre-delivery window (heterogeneity, P = .007). Read More

The authors aimed to examine time trends in national perinatal outcomes in pregnancies complicated by pre-existing type 1 or type 2 diabetes. They analysed episode-level data on all obstetric inpatient delivery events (live or stillbirth) using the Scottish Morbidity Record (SMR02). The number of pregnancies complicated by diabetes increased significantly, by 44% in type 1 diabetes and 90% in type 2 diabetes, across the 15 years examined, to rates of 1 in 210 and 1 in 504 deliveries, respectively. The authors concluded that women with diabetes are receiving increased intervention in pregnancy (earlier delivery, increased Caesarean section rates), but despite this, higher birthweights are being recorded.Read More

The authors aimed to synthesize the published literature on the association between HDP and risk of neurodevelopmental disorders in offspring in a systematic review and meta-analysis. Of 1166 studies identified, 61 unique articles met inclusion criteria. Twenty studies reported estimates for ASD. Eleven of these (including 777 518 participants) reported adjusted estimates, with a pooled adjusted OR of 1.35 (95% CI, 1.11-1.64). Ten studies reported estimates for ADHD. Six of these (including 1 395 605 participants) reported adjusted estimates, with a pooled adjusted OR of 1.29 (95% CI, 1.22-1.36). Individual estimates reported for these were largely inconsistent, with few patterns of association observed.Read More

The authors conducted a nested control study within the Quebec Pregnancy Cohort. For each case of SA, we selected 10 controls at the index date that were matched on gestational age and year of pregnancy. TMP-SMX exposure was defined as either having filled at least one prescription between the first day of gestation (1DG) and the index date, or as having filled a prescription before pregnancy but with a duration overlapping the 1DG (102 pregnancies exposed to TMP-SMX, including 25 cases of SA and 77 controls). Adjusting for potential confounders, TMP-SMX exposure was associated with an increased risk of SA (AOR 2.94, 95% C 1.89-4.57, 25 exposed cases).Read More

The authors aimed to investigate the association between in-utero lithium exposure and risk of pregnancy complications, delivery outcomes, neonatal morbidity, and congenital malformations. Pregnancies were grouped into a lithium-exposed group and a mood disorder reference group. Lithium exposure was not associated with any of the predefined pregnancy complications or delivery outcomes. An increased risk for neonatal readmission within 28 days of birth was seen in the lithium-exposed group compared with the reference group (pooled prevalence 27·5% [95% CI 15·8-39·1] vs 14·3% [10·4-18·2]; pooled aOR 1·62, 95% CI 1·12-2·33). Lithium exposure during the first trimester was associated with an increased risk of major malformations (pooled prevalence 7·4% [95% CI 4·0-10·7] vs 4·3% [3·7-4·8]; pooled aOR 1·71, 95% CI 1·07-2·72) but for major cardiac malformations the difference was not significant (2·1% [0·5-3·7] vs 1·6% [1·0-2·1]; pooled aOR 1·54, 95% CI 0·64-3·70). Read More

The authors compared associations between interpregnancy intervals (IPIs) and adverse perinatal outcomes in deliveries following IVF with deliveries following spontaneous conception or other (non-IVF) fertility treatments. They established a cohort using linked birth certificate and assisted reproductive technology surveillance data from Massachusetts and Michigan and assessed associations between IPI and preterm birth (PTB), low birth weight (LBW), and small for gestational age (SGA) according to live birth or nonlive pregnancy outcome in the previous pregnancy. The authors concluded that following live births, IPIs <12 or ≥60 months were associated with higher risks of most adverse perinatal outcomes in both IVF and non-IVF deliveries. Read More

The authors examined the risk of developing gestational diabetes associated with the continuation of treatment with aripiprazole, ziprasidone, quetiapine, risperidone, and olanzapine during pregnancy compared with discontinuation of these antipsychotic drugs. Among 1,543,334 pregnancies, some expectant mothers at baseline were receiving treatment with aripiprazole (N=1,924), ziprasidone (N=673), quetiapine (N=4,533), risperidone (N=1,824), or olanzapine (N=1,425). The adjusted relative risks were 0.82 (95% CI=0.50-1.33) for aripiprazole, 0.76 (95% CI=0.29-2.00) for ziprasidone, 1.28 (95% CI=1.01-1.62) for quetiapine, 1.09 (95% CI=0.70-1.70) for risperidone, and 1.61 (95% CI=1.13-2.29) for olanzapine. Compared with women who discontinued use of an atypical antipsychotic medication before the start of pregnancy, women who continued treatment with olanzapine or quetiapine had an increased risk of gestational diabetes that may be explained by the metabolic effects associated with these two drugs.

In this study, the authors investigated if fluconazole use during pregnancy is associated with stillbirth and neonatal death. From a cohort of 1 485 316 pregnancies, 10 669 exposed and 106 690 unexposed pregnancies were included in the matched analysis of stillbirth, and 10 640 exposed and 106 387 unexposed pregnancies in the matched analysis of neonatal death. There were 2.7 stillbirths per 1000 exposed pregnancies and 3.6 per 1000 unexposed pregnancies (HR, 0.76 [95% CI,0.52-1.10]), and 1.2 neonatal deaths per 1000 exposed pregnancies and 1.7 per 1000 unexposed pregnancies (RR, 0.73 [95% CI, 0.42-1.29]; Table 2). Results were similar for doses of 300 mg or less and for more than 300 mg. Read More

Using a population-based cohort of nulliparous women in British Columbia, Canada, the authors examined relationships between maternal age and pregnancy outcomes using logistic regression. They found that risks of hypertensive disorders increased gradually until age 35, then accelerated. Risk of multiple gestations, major congenital anomalies, and maternal mortality or severe morbidity increased slowly until age 30, then accelerated. Cesarean delivery and gestational diabetes risks increased linearly with age. While indicated preterm delivery increased rapidly with maternal age, spontaneous preterm delivery did not. Stillbirth, neonatal mortality, and infant mortality had j-shaped relationships with maternal age, with nadirs near 30.Read More

JAMA. 2018 May 1;319(17):1773-1780. doi: 10.1001/jama.2018.4072.The authors compared oral glyburide vs subcutaneous insulin in prevention of perinatal complications in newborns of women with gestational diabetes. Women who required pharmacologic treatment after 10 days of dietary intervention were randomly assigned to receive glyburide (n=460) or insulin (n=454). Among the 914 patients who were randomized (mean age, 32.8 [SD, 5.2] years), 98% completed the trial. In a per-protocol analysis, 367 and 442 women and their neonates were analyzed in the glyburide and insulin groups, respectively. The frequency of the primary outcome was 27.6% in the glyburide group and 23.4% in the insulin group, a difference of 4.2% (1-sided 97.5% CI, -∞ to 10.5%; P=.19). This study of women with gestational diabetes failed to show that use of glyburide compared with subcutaneous insulin does not result in a greater frequency of perinatal complications.Read More

Risk of preterm delivery and small-for-gestational-age births in women with autoimmune disease using biologics before or during pregnancy: a population-based cohort study.Tsao NW, Sayre EC, Hanley G, Sadatsafavi M, Lynd LD, Marra CA, De Vera MA.Ann Rheum Dis. 2018 Jun;77:869-874. doi: 10.1136/annrheumdis-2018-213023. Epub 2018 Mar 1.The authors aimed to assess the risk of preterm delivery and small-for-gestational-age (SGA) births in women with autoimmune diseases using biologics before or during pregnancy. In unadjusted analyses, the ORs for the association of biologics exposure with preterm deliveries were 1.64 (95% CI 1.02 to 2.63) and 1.34 (95% CI 0.72 to 2.51) for SGA. After HDPS matching with 600 unexposed pregnancies, the ORs for the association of biologics exposure and preterm deliveries were 1.13 (95% CI 0.67 to 1.90) and 0.91 (95% CI 0.46 to 1.78) for SGA. Sensitivity analyses using HDPS deciles, continuous HDPS covariate or longer exposure window did not result in marked changes in point estimates and CIs. Read More

The authors aimed to assess the association between fetal exposure to antibiotics and obesity at ages 4 and 7 years. Prenatal exposure to antibiotics repeatedly was associated with childhood obesity at age 7 years, and risk of obesity tended to increase with an increasing number of antibiotic exposures (2-3 times: RR = 1.22, 95% CI [CI]: 1.04, 1.44; ≥ 4 times: RR = 1.34, 95% CI: 1.03, 1.73). The magnitude of association was strongest for repeated exposures in second trimester (RR = 1.40, 95% CI = 1.16, 1.71). Prenatal antibiotic use was not associated with obesity or BMI z-score at age 4 years. These findings support an increased risk of mid-childhood obesity with repeated use of antibiotics during pregnancy.Read More

The aim of this study is to assess the association between the use of antidepressants during pregnancy and the risk of developing gestational hypertension. They found that the risk of gestational hypertension was doubled for women using antidepressant (aOR 2.00 95% CI 1.28-3.13). Significant associations were also found for the subgroup selective serotonin reuptake inhibitors (SSRIs) (aOR 2.07 95% CI 1.25-3.44), ≥30 DDDs (aOR 2.50 95% CI 1.55-3.99) and maternal age of 30-34 years (aOR 2.59 95% CI 1.35-4.98). Varying the theoretical gestational age showed comparable results. Read More

Using individual-level data from the Danish National Prescription Registry (2000-2015), the authors provided detailed descriptions of treatment patterns at the individual level, stratified by age (0-1 years, 2-4 years) and antibiotic substance. The incidence rate was relatively stable between 2000 and 2010, after which it dropped by 37% until 2015. The authors concluded that considerable variation is seen in the utilization of topical ocular antibiotics among children in Scandinavia, with Denmark having the highest use.Read More

Using 2013-2014 TruvenHealth MarketScan data, the authors calculated an AMR (number of controller medications / [number of controller medications + number of rescue medications]) for each rolling 3-month period and each rolling 6-month period. Using logistic regression, authors tested how a rolling AMR predicted a child's hospitalization or emergency department (ED) visit for asthma. A higher proportion of patients with high-risk AMRs (9.6% and 9.5%, respectively) had an ED visit or hospitalization compared with patients with low-risk (5.0% and 5.7%) and missing (3.5% and 3.2%) AMRs (P <.0001).Read More

The authors aimed to study topical corticosteroid use in Dutch asthmatic children using pharmacy dispensing data and to assess whether Dutch physicians prescribe topical corticosteroids in this population according to clinical guidelines. The study found that there is a statistically significantly higher prescription rate of topical corticosteroid for infants, and sometimes general practitioners prescribe more-potent topical corticosteroids without a prior prescription of the same potency by a specialist. Read More

The authors estimated the proportion of pediatric patients who were treated with nonsteroidal anti-inflammatory drugs, cyclooxygenase-2 (COX-2) inhibitors, opioids (immediate release or extended release), antidepressants, topical analgesics, anticonvulsants, and other therapies based on a large, real-world sample using data from the Truven Health MarketScan® Research Databases. The types of pain treatments varied substantially by condition and age of the patient, with the highest prevalence of use in older children. Read More

The study’s objective was to estimate SSRI adherence in children with anxiety disorders and determine if prior parental medication adherence is predictive of child high SSRI adherence. Overall 64% of children had high adherence if their parent had high SSRI adherence versus 53% of children with parents with low SSRI adherence (RD, 12%; multivariable risk ratios, 1.17; 95% confidence interval, 1.14-1.20). Findings were similar for parent statin (RD=10%) and antihypertensive adherence (RD=8%) and when stratified by child age and parent sex. Read More

The authors used electronic health record (EHR) data from 2 pediatric health systems (2011-2013) to estimate the risk of arrhythmia associated with inhaled short-acting beta-2 agonists (SABA) in pediatric patients and (2) determine whether risk varied by on-label versus off-label prescribing. Using propensity score methodology, the authors found that the adjusted risk for arrhythmia was increased among exposed children (OR 1.89, 95% CI 1.31-2.73 in health system 1; OR 1.26, 95% CI 0.30-5.33 in health system 2) without evidence of interaction between label status and risk. Read More

Oral fluoroquinolone prescribing to children in the united states from 2006 to 2015Etminan M, Guo M, Carleton BPediatr Infect Dis J. 2018 May 24. doi: 10.1097/INF.0000000000002121. [Epub ahead of print]

Fluoroquinolone (FQ) prescription rates have increased over the last 10 years despite recent warnings of serious adverse. Drug prescription data from the PharMetrics Plus™ health claims database (United States) were analyzed to examine dispensing of ciprofloxacin, levofloxacin, moxifloxacin, ofloxacin, or gemifloxacin to children from 2006 to 2015. The study suggests an increase in the prescribing of FQs, mostly ciprofloxacin, over a ten-year period although numbers have decreased slightly in 2014 and 2015. At least one in five prescriptions were deemed unnecessary. Read More

The study examined the association of furosemide therapy with the incidence of bone fractures in children with congenital heart disease using data from the 2008-2014 Texas Medicaid databases. Propensity score matching was used to compare furosemide adherent, furosemide nonadherent, and no furosemide users. Both furosemide groups were more likely to have fractures than the no furosemide group: furosemide-adherent OR of 1.9 (95% CI, 1.17-2.98; P = .009); furosemide nonadherent OR of 1.5 (95% CI, 1.10-2.14; P = .01). Read More

Studies on adolescent drug use are scarce as most studies do not distinguish between children and adolescents. Therefore, authors assessed overall drug use in adolescents (12-18 years) using pharmacy dispensing records from 62 community pharmacies in the Netherlands. Of the adolescents who collected at least one medication prescription, half of them collected dermatologicals (46.2% males; 52.3% females), followed by drugs for the respiratory system (43.4% males; 40.3% females) and anti-infectives for systemic use (31.3% males; 39.1% females).Read More

The authors integrated all the randomized evidence from the available antipsychotics used for this subgroup by performing a network-meta-analysis and pairwise meta-analysis. Twenty-eight RCTs with 3003 unique participants (58% males; mean age 14.41 years) published from 1967 to 2017 were identified. Clozapine was significantly more effective than all other analyzed antipsychotics. There were evidence gaps for some drugs and many outcomes, especially safety outcomes. The available evidence showed that the treatment effects were similar compared to findings in adult patients with schizophrenia.Read More

There are substantial gaps in evidence regarding the safety of many drugs in children. Real-world data could help to fill these gaps in several ways. First, such data can provide greater insight into the long-term effects of in utero exposure to medicines on growing children. Similarly, real-world data can inform our understanding of the long-term effects of exposure to medicines early in children’s development… As efforts to advance the use of real-world data to generate real-world evidence move forward, it is imperative that investigators not treat the use of medication in children as an afterthought.Read More

In this retrospective cohort study, the incidence and risk of dystonia in children and adolescents treated with atomoxetine was compared to a propensity score-matched cohort of stimulant users. There was no significant difference in incidence or risk of dystonia among patients treated with atomoxetine compared to stimulants (HR = 0.68; 95% CI: 0.36 - 1.28; P = 0.23). Read More

The authors conducted a systematic review (n=13 studies) and meta-analysis (n=8 studies) of observational studies investigating the association between antibiotic exposure in infancy and risk of childhood overweight and obesity. Exposure to antibiotics in infancy was associated with an increased odds ratio (OR) of childhood overweight and obesity (OR 1.11, 95% confidence interval [CI] 1.02-1.20). Exposure to >1 treatment was associated with an OR of 1.24 (95% CI 1.09-1.43) and exposure within the first 6 months of life was associated with an OR of 1.20 (95% CI 1.04-1.37). It is unclear whether this association is mediated via direct effects of antibiotics on the gut microbiota. Read More

The authors evaluated the clinical effectiveness of influenza vaccination for children aged 1-15 years in Japan throughout four influenza seasons from 2010 to 2014 using a large-scale claims database for employee health care insurance plans. Throughout the four seasons, the estimated ORs for influenza onset were statistically significant and ranged from 0.797 to 0.894 after doubly robust adjustment. The study confirmed the clinical effectiveness of influenza vaccination in children aged 1-15 years from the 2010/2011 to 2013/2014 influenza seasons.Read More

The authors constructed ten two-year cohorts of Medicaid beneficiaries between ages 0 and 17 years who received at least one psychotropic to treat a mental disorder from 1999 to 2010. Polypharmacy was defined as any period in which dispensed days' supply of psychotropics overlapped for more than 45 days. The prevalence of any-class and multiclass psychotropic polypharmacy grew steadily, from 21.2% and 18.8% in 1999-2000 to 27.3% and 24.4% in 2009-2010, respectively. Heterogeneous prevalences of psychotropic polypharmacy were noted across states. Read More

Parents of 462 children followed in a pediatric epilepsy clinic were surveyed regarding prior authorization in the preceding year. Prior authorization proceeded smoothly in only 31 (49.2%) cases. Twenty-three (36.5%) children experienced a delay of seven days or more in starting a new drug, and 24 (38.1%) experienced a lapse in coverage of their current medication. Of the 11 whom missed doses, seven had increased seizures, and one required hospital admission for status epilepticus. Prior authorization of antiepileptic drugs is common but problematic.Read More

September 2018

Pregnancy

Adverse pregnancy outcomes associated with gestational exposure to antiepileptic drugs.Andrade C.J Clin Psychiatry. 2018 Jul 31;79. pii: 18f12467. doi: 10.4088/JCP.18f12467.​Major congenital malformation risks in association with gestational exposure to antiepileptic drugs (AEDs) have been extensively studied. Less information is available on other adverse outcomes associated with the use of these drugs during pregnancy. This article examined the risk of fetal loss, intrauterine growth retardation (IUGR), and preterm birth following gestational exposure to 14 AEDs, based on information obtained from a recent network meta-analysis of mostly nonrandomized, observational studies. The results showed that very few AEDs are significantly associated with each adverse outcome and that the implicated AEDs are different for different outcomes. Read More

A follow-up questionnaire on maternal health was distributed within the Danish National Birth Cohort (established in 1996-2002) 14 years after the index birth. To ensure the appropriate use of these data, the possibility of selection bias due to nonparticipation had to be evaluated. The authors estimated 4 selected exposure-outcome associations and calculated relative ORs for the relationship between the baseline cohort and the subset participating in the Maternal Follow-up. The authors concluded that selection bias in the chosen scenarios was limited; ratios of the ORs ranged from -14% to 5% after adjustment. Read More

Despite the potential impact of untreated hypothyroidism on infant neurodevelopment, few studies have investigated the risk factors associated with discontinuation of thyroid hormone replacement therapy (THRT) in pregnancy. The authors aimed to identify such factors in a population of women using THRT prior to pregnancy. Of 86 848 enrolled pregnant women, 1587 used THRT prior to pregnancy. Of these, 207 (13.0%) discontinued THRT during early pregnancy. For discontinuers, non-medicated mental comorbidity and non-compliance with nutritional supplements presented increased risk, whereas having a medicated somatic disorder was protective. Read More

Fetal exposure to infectious and noninfectious diseases may influence early childhood developmental functioning, on the path to later mental illness. The authors investigated the effects of in utero exposure to maternal infection and noninfectious diseases during pregnancy on offspring developmental vulnerabilities at age 5 years. The authors discovered that maternal infectious diseases during pregnancy and early childhood infection conferred the largest associations with developmental vulnerabilities at age 5 years; maternal noninfectious illness during pregnancy also retained small but significant associations with developmental vulnerabilities after adjustment. Read More

Many patients with autoimmune hepatitis are women of fertile age. The authors aimed to conduct a nationwide study on risk of miscarriage, birth rate, and birth outcomes in women with autoimmune hepatitis. The author found that the risk of miscarriage was similar in women with autoimmune hepatitis and controls: RR 1.16 (95% CI 0.80-1.69). The first-time birth rate, including singleton and multiple births, per 1000 person-years in women with autoimmune hepatitis was 37 (95% CI 29-46), in controls 32 (95% CI 30-35). Women with autoimmune hepatitis had an increased risk of preterm birth (adjusted OR 3.19, 95% CI 1.53-6.64) and small for gestational age babies (adjusted OR = 3.20, 95% CI 0.33-31.29), but not of congenital malformations (adjusted OR = 1.27, 95% CI 0.48-3.34) or stillbirth. Read More

Previous studies have suggested a positive association between self-reported maternal acetaminophen use during pregnancy and risk of attention deficit hyperactivity disorder (ADHD) in offspring. The authors sought to examine the prospective association between maternal plasma biomarkers of acetaminophen intake and ADHD diagnosis in the offspring. Compared to neurotypical children, the authors observed significant positive dose-responsive associations with ADHD diagnosis for each maternal acetaminophen biomarker. These dose-responsive associations persisted after adjusting for indication of acetaminophen use and other pertinent covariates; and were specific to ADHD, rather than other neurodevelopmental disorders. Read More

Obstet Gynecol. 2018 Jul;132:35-44. doi: 10.1097/AOG.0000000000002694.Within a retrospective observational cohort, the authors compared risks for spontaneous abortion after 4vHPV in three exposure windows: distal (16-22 weeks before the last menstrual period [LMP]), peripregnancy (within 6 weeks before the LMP), and during pregnancy (LMP through 19 weeks of gestation). Spontaneous abortion risk after 4vHPV peripregnancy or 4vHPV during pregnancy was compared with distal vaccination using Cox models respectively. The authors found that the risk of spontaneous abortion was not increased among women who received 4vHPV during pregnancy (adjusted HR 1.10, 95% CI 0.81-1.51) or peripregnancy 1.07 (0.81-1.41). Read More

Animal evidence suggests that endocrine disruptors affect germline cells and neurodevelopment. The authors aimed to explore the potential consequences of exposure to diethylstilbestrol or DES across generations-specifically, third-generation neurodevelopment. The 3 generations analyzed in this study were the participants (F1 generation), their mothers (F0 generation), and their live-born children (F2 generation). Use of diethylstylbestrol by F0 mothers was associated with an increased risk of ADHD among the F2 generation: 7.7% vs 5.2%, adjusted OR (OR), 1.36 (95% CI, 1.10-1.67) and an OR of 1.63 (95% CI, 1.18-2.25) if diethylstilbestrol was taken during the first trimester of pregnancy. No effect modification was observed by the F2 children's sex. Read More

The 2003 revision of the US Certificate of Live Birth added specific checkbox items on severe maternal morbidity occurring within 24 hours of delivery. The items included maternal transfusion, third- or fourth-degree perineal laceration, ruptured uterus, unplanned hysterectomy, and admission to the intensive care unit. The authors designed a population-based study of all live births in Massachusetts linked to hospital discharge data to validate those maternal complications. They found that the birth certificate greatly underreported severe maternal morbidity, with sensitivities ranging from 0.11 (transfusion in vaginal births) to 0.52 (hysterectomy after cesarean delivery). The PPV ranged from 0.03 to 0.90, with highest values for transfusion and perineal lacerations. The specificity was >99%, and the negative predictive value was >98% in all cases. Read More

Despite the labeling, anti-tumor necrosis factor (TNF) antibodies (anti-TNFα) are increasingly being used during pregnancy. The authors aimed to assess the safety of anti-TNFα treatment in pregnant women with IBD and their children. The authors found that anti-TNFα treatment was associated with a higher risk of overall maternal complications (adjusted Odds Ratio (aOR) = 1.49; 95% CI (CI): 1.31-1.67) and infections (aOR = 1.31; 95% CI: 1.16-1.47). Maintaining anti-TNFα after 24 weeks did not increase the risk of maternal complication, but interrupting the anti-TNFα increased relapse risk. No increased risk for infection was found in children (aOR = 0.89; 95% CI: 0.76-1.05) born to mother exposed to anti-TNFα during pregnancy. Read More

In this large observational study, the authors aimed to examine the risk of postpartum hemorrhage (PPH) and neonatal bleeding complications associated with late-pregnancy exposure to anticonvulsant drugs (ACDs) that induce cytochrome P450 enzymes (ACDi) and alter the metabolism of vitamin K compared to other ACDs. Among 11,572 women with an ACD prescription overlapping delivery, 2.6% (135/5,109) in the ACDi group and 3.6% (231/6,463) in the other ACDs group had a diagnosis of PPH: unadjusted RR 0.74 (95% CI 0.60-0.91), adjusted RR 0.77 (95% CI 0.58-1.00). The prevalence of neonatal bleeding complications was 3.1% (157/5,109) in the ACDi group and 3.5% (229/6,463) in the other ACDs group: unadjusted RR 0.87 (95% CI 0.71-1.06), adjusted RR 0.83 (95% CI 0.64-1.08). Read More

In this study, the authors aimed to determine the associations between maternal diabetes and in-hospital mortality, as well as neonatal morbidity in very preterm infants with a birth weight of less than 1500 g. Of 76 360 infants, 25 962 (34%) and 33 598 (44%) were born before 28 weeks of gestation to mothers with and without diabetes, respectively. Infants of mothers with diabetes were born at a later GA than infants of mothers without diabetes. In adjusted analyses, no significant differences in in-hospital mortality (adjusted OR, 1.16 (95% CI, 0.97-1.39) or the composite of mortality and severe morbidity (adjusted OR, 0.99 (95% CI, 0.88-1.10) were observed. With few exceptions, outcomes of infants born to mothers with and without diabetes were similar regardless of infant sex, GA, or country of birth. Read More

Research on the developmental origins of health and disease (DOHaD) has traditionally focused on how maternal exposures around the time of pregnancy might influence offspring health and risk of disease. The authors acknowledge that for some exposures this is likely to be correct, but argue that the focus on maternal pregnancy effects also reflects implicit and deeply-held assumptions that 1) causal early life exposures are primarily transmitted via maternal traits or exposures, 2) maternal exposures around the time of pregnancy and early infancy are particularly important, and 3) other factors, such as paternal factors and postnatal exposures in later life, have relatively little impact in comparison. These implicit assumptions about the "causal primacy" of maternal pregnancy effects set the agenda for DOHaD research and, through a looping effect, are reinforced rather than tested. The authors propose practical strategies to redress this imbalance through maintaining a critical perspective about these assumptions. Read More

Inference in epidemiologic studies is plagued by exposure misclassification with several existing methods to correct for misclassification error. One approach is to use point estimates for the sensitivity (Sn) and specificity (Sp) of the tool used for exposure assessment. Unfortunately, typically the Sn and Sp are not known with certainty. Bayesian methods for exposure misclassification correction allow us to model this uncertainty via distributions for Sn and Sp. The authors illustrated an occupational epidemiology application of a Bayesian approach to correct for the differential misclassification error generated by estimating occupational exposures from job codes using a job exposure matrix (JEM). The authors argued that analyses accounting for exposure misclassification should become more commonplace in the literature. Read More

The authors aimed to characterize patterns of biologics use and discontinuation before and during pregnancy in women with autoimmune diseases in British Columbia, Canada. The use of biologics in this cohort increased from 0% in 2002 to 5.7% by 2012 (P < 0.001). Within the first trimester of pregnancy, 31% of women (34/110) discontinued their biologic treatment, and 38% (30/79) discontinued use in the second trimester, while 98% of those receiving treatment in the second trimester (50/51) continued treatment in the third trimester. Women with rheumatoid arthritis had three times higher odds (OR 3.40 [95% CI1.33-8.71]) of discontinuing biologics during pregnancy, compared to those with inflammatory bowel disease. Read More

The authors aimed to optimize an existing algorithm for the identification and classification of pregnancy outcomes in the German Pharmacoepidemiological Research Database (GePaRD) with a particular focus on births. The algorithm identified 1,235,261 pregnancy outcomes in the database, with the majority (94%) being live births, classified as preterm (10%), term (78%), and (12%) births after the expected delivery date. Implausible sequence of outcomes (for example, an induced abortion within a pregnancy categorized as ending in a live birth) were rare (0.03%). Read More

The authors assessed the risk of incident cardiovascular events that led to hospitalizations or emergency department visits following atypical antipsychotic (AAP) treatment initiation in youth. Medicaid claims were used to conduct a retrospective cohort study of youth (5-20 years) who initiated AAP treatment. During follow-up, the risk of cardiovascular events was significantly greater during current than former AAP use (RR = 1.55, 95% CI = 1.09-2.21). The risk intensified with increasing dose and with concomitant SSRI/SNRI use. Read More

This study analyzed the masking effect of vaccines in pediatrics in the EudraVigilance database by conducting disproportionality analysis in the full database (containing vaccine exposures) and in a restricted set (excluding vaccine exposures). Removal of vaccines decreased the reporting odds ratio (ROR) values both in negative and positive controls. The authors recommend stratification by age and removal of vaccine exposures if the investigated adverse drug reactions include those typically reported in association with vaccines for the age strata. Read More

IBM MarketScan commercial and Medicaid claims data were used to measure days' supply among adolescents (2005-2016). For adolescents, fills of prescription opioids generally exceeded three days. Efforts to reduce opioid prescribing through guidelines, prescription drug monitoring programs, and limits on days' supply do not appear to have affected prescribing for adolescents as much as desired. Read More

This study aimed to investigate the utilization of antiepileptic drugs (AEDs) in children and adolescents (0-17 years) with epilepsy and other diagnoses in a nationwide population between 2007 and 2014 using data from the Swedish Prescribed Drug Register and the National Patient Register. Epilepsy was the most frequent diagnosis (46%) recorded within the year prior to the first AED dispensing. Psychiatric and pain diagnoses were more common in girls. Individual AEDs used seems to be in accordance with approved indications. However, the use of AED on non-epilepsy diagnoses, especially pain disorders, raises concerns. Read More

This study analyzed data on the use of Supprelin and Lupron reported to the Pediatric Health Information System (PHIS) from 2013 to 2016 to determine the trends in both the FDA-approved and off-label uses of these medications. The fraction of children receiving therapy for an off-label indication more than doubled, from 12% to 29%. Privately insured patients were more likely to be treated for an off-label indication (13%) than Medicaid patients (8%). Read More

This study aimed to estimate the cumulative proportion of concomitant antipsychotic (AP)/ methylphenidate (MPH) use in children and adolescents with ADHD. The cumulative proportion of individuals with any AP/MPH combination therapy rose to over 6% within 9 years after initiating MPH. The proportion of individuals with potentially appropriate use was high (>72%) in risperidone/MPH and tiapride/MPH and low (15%) in pipamperone/MPH combination users. ADHD guidelines should specify algorithms concerning the use of AP medication. Read More

The authors describe medication safety and implementation challenges and solutions in the pediatric population of a large academic center transitioning its EHR to Epic. After implementation, there was a 5-fold increase in the overall number of medication safety reports; by the third month the rate of reported medication errors had returned to baseline. Three major safety themes arose: (1) enterprise logic in rounding of doses and dosing volumes; (2) ordering clinician seeing a concentration and product when ordering medications; and (3) the need for standardized dosing units through age contexts created issues with continuous infusions and pump library safeguards. Read More

Concomitant use of psychotropic medication with stimulants for the treatment of ADHD in children and adolescents: a retrospective insurance claims study in the united states.Zhou Z, Betts KA, Bocharova I, Kinrich D, Spalding WMJ Atten Disord. 2018 Jul 1:1087054718784668. doi: 10.1177/1087054718784668.​This study evaluated annual concomitant psychotropic medication use among stimulant-treated children (6-12 years) and adolescents (13-17 years) with ADHD from 2011-2014. Annual period prevalence of any concomitant psychotropic medication use was 22.9% to 25.0% for children and 25.2% to 28.2% for adolescents. The most common medication categories included selective serotonin reuptake inhibitors, atypical antipsychotics, and guanfacine extended release. Read More​

OCtober 2018

Pregnancy

Longitudinal trajectories of antidepressant use in pregnancy and the postnatal period.Bandoli G, Kuo GM, Sugathan R, Chambers CD, Rolland M, Palmsten K.Arch Womens Ment Health. 2018 Aug;21:411-419. doi: 10.1007/s00737-018-0809-2.The authors performed longitudinal trajectory modeling to describe patterns of antidepressant use in the first 32 weeks of pregnancy, and test whether these trajectories are associated with a reduction in birth weight or gestational age at delivery. The authors clustered women with similar utilization patterns using k-means longitudinal modeling. Relative to the lowest trajectory group, the highest trajectory group during pregnancy was associated with reduced birth weight in multivariable analysis (average daily highest trajectory vs. lowest trajectory β - 314.1 g, 95% CI - 613.7, - 15.5) adjusted for depression severity score, maternal age, race, and pregnancy smoking. Trajectory groups were not associated with gestational age at delivery. Read More

This study was aimed to determine the prevalence of opioid use before, during, and after pregnancy and describe its use based on patient-specific characteristics in a large Upper Midwest integrated health care system from July 1, 2006 through June 30, 2014. From 11,565 deliveries among 9690 unique women, 862 (7.5%) deliveries were associated with significant opioid use. Significant opioid use was associated with single marital status, Cesarean section, Medicaid coverage, tobacco use, depression, anxiety, bipolar disorder, substance use disorder, nonopioid analgesic use, and referral to physical therapy, psychotherapy, or pain specialists. From 2006 to 2014 opioid use decreased from 9% to 6% before, during, and after pregnancy with a rate of change per year of -0.2%. Read More

Maternal infection during pregnancy (IDP) has been associated with increased risk of attention-deficit/hyperactivity disorder (ADHD) in offspring. However, infection is associated with social adversity, poor living conditions and other background familial factors. As such, there is a need to rule out whether the observed association might be attributed to such confounding. In this study, the authors found that maternal IDP was associated with ADHD in offspring (HR = 2.31, 2.04-2.61). This association was attenuated when accounting for measured covariates (HR = 1.86, 1.65-2.10). The association was further attenuated when adjusting for unmeasured factors shared between cousins (HR = 1.52, 1.12-2.07). Finally, the association was fully attenuated in sibling comparisons (HR = 1.03, 0.76-1.41). Read More

This study was aimed to examine the association between prenatal exposure to β2AAs and the risk of childhood cerebral palsy (CP). Children born to mothers who used β2AAs from 30 days before pregnancy until delivery were categorized as the exposed. Among all the 442,278 singletons, the risk of childhood CP was 0.21% in exposed and 0.19% in unexposed group, yielding an aOR 1.12 (0.82 - 1.53). When extending the exposure time window to 2 years prior to pregnancy, no overall significant association was observed regardless of the exposure period. However, an increased risk of CP (aOR = 1.41, 0.92 - 2.18) for maternal β2AAs use during pregnancy was observed in female offspring, especially in those born at term (aOR = 1.65, 1.02 - 2.67). This increase was mainly attributed to an increased risk in those born to mothers who used β2AAs both before and during pregnancy (aOR = 1.81, 0.99 - 3.33). Read More

The authors aimed to synthesize the published literature on the association between hypertensive disorders of pregnancy (HDP) and risk of neurodevelopmental disorders in offspring in a systematic review and meta-analysis. The authors conducted random-effects meta-analyses of estimated pooled odds ratios (ORs) for HDP and ASD and for HDP and ADHD. Of 1166 studies identified, 61 unique articles met inclusion criteria. Twenty studies reported estimates for ASD. Eleven of these reported adjusted estimates, with a pooled adjusted OR of 1.35 (95% CI, 1.11-1.64). Ten studies reported estimates for ADHD. Six of these reported adjusted estimates, with a pooled adjusted OR of 1.29 (95% CI, 1.22-1.36). Thirty-one studies met inclusion criteria for all other neurodevelopmental disorders. Individual estimates reported for these were largely inconsistent, with few patterns of association observed. Read More

This study was aimed to assess the extent to which multiple gestations mediate risk of pregnancy complications from fertility treatment and to address possible confounding by the underlying infertility. Compared with pregnancies achieved without any assistance, those having received some treatment had higher odds of all studied complications except gestational diabetes. Associations with placenta previa (OR 2.17, 1.95-2.40) and placental abruption (OR 1.77, 1.54-2.03) were almost entirely independent of multiple gestations. In contrast, the majority of the associations with preterm birth (OR 1.69, 1.62-1.77), caesarean delivery (RR 1.15, 1.13-1.17) and pre-eclampsia (OR 1.17, 1.11-1.22) were mediated by multiple gestations (87%, 62% and 91% of the effect mediated, respectively). Both direct and mediated pathways contributed to the remaining positive associations with chorioamnionitis, labour induction and postpartum haemorrhage. Read More

Ondansetron for treatment of nausea and vomiting of pregnancy and the risk of specific birth defects.Parker SE, Van Bennekom C, Anderka M, Mitchell AA; National Birth Defects Prevention Study.Obstet Gynecol. 2018 Aug;132:385-394. doi: 10.1097/AOG.0000000000002679.The authors used data from two case-control studies, the National Birth Defects Prevention Study (1997-2011) and the Slone Birth Defects Study (1997-2014) to describe time trends in ondansetron use and to investigate associations between first-trimester ondansetron use and major birth defects. Among women in the control group, ondansetron exposure increased from less than 1% before 2000 to 13% in 2013-2014. Ondansetron use was not associated with an increased risk for most of the 51 defect groups analyzed. Modest increases in risk were observed for cleft palate (adjusted OR 1.6, 95% CI 1.1-2.3) in the National Birth Defects Prevention Study and renal agenesis-dysgenesis (adjusted OR 1.8, 95% CI 1.1-3.0) in the Birth Defects Study, although these findings may be the result of chance. Read More

The authors examined associations between maternal opioid prescriptions preconception to delivery (peri-pregnancy) and child's risk of ASD, developmental delay/disorder (DD) with no ASD features, or ASD/DD with autism features in the Study to Explore Early Development, a case-control study of neurodevelopment. Preconception opioid prescription was associated with 2.43 times the odds of ASD (95% CI 0.99, 6.02) and 2.64 times the odds of ASD/DD with autism features (95% CI 1.10, 6.31) compared to mothers without prescriptions. Odds for ASD and ASD/DD were non-significantly elevated for first trimester prescriptions. Read More

Implications of changes in FDA prescribing information regarding the safety and use of asthma biologics during pregnancy.Schatz M, Krishnan JA, Chambers C.Ann Am Thorac Soc. 2018 Aug 21. doi: 10.1513/AnnalsATS.201806-400PP.Many lung diseases occur in women of childbearing age, and treating these conditions requires knowledge of the safety of the treatments during pregnancy as well as understanding the risks of the disease itself for the mother and the infant. An important source of this information has been the U.S. Food and Drug Administration (FDA)-approved Prescribing Information. The FDA revised the format of the pregnancy information provided in the Prescribing Information by instituting the Pregnancy and Lactation Labeling Rule (PLLR) on June 1, 2015. This Perspective provides a description of the new FDA Prescribing Information format for medication safety during pregnancy and then discusses asthma, the most common pulmonary condition in pregnant women, as a use case. Read More

Pediatrics ​

Filled prescriptions of age-related contraindicated drugs in children: a one-year nationwide cohort study in the Netherlands.Cheung K, Teichert M, Moll HA, Stricker BH, Visser LEInt J Clin Pharm. 2018 Aug 23. doi: 10.1007/s11096-018-0717-6. The authors examined the incidence and prevalence of contraindicated drugs that were dispensed for the use by children (age <17 years) using routinely collected data from 95% of all community pharmacies in the Netherlands in 2016. 3.9% of all children received at least one drug that was contraindicated for their age. The highest percentage of contraindicated drugs was observed in patients aged 1-2 years and 13-17 years (7.0 and 5.7%, respectively) and the percentage was higher in females compared to males (4.3 and 3.6%, respectively; p value < 0.001). Read MoreComparative efficacy and tolerability of medications for attention-deficit hyperactivity disorder in children, adolescents, and adults: a systematic review and network meta-analysis.Cortese S, Adamo N, Del Giovane C, Mohr-Jensen C, Hayes AJ, Carucci S, Atkinson LZ, Tessari L, Banaschewski T, Coghill D, Hollis C, Simonoff E, Zuddas A, Barbui C, Purgato M, Steinhausen HC, Shokraneh F, Xia J, Cipriani ALancet Psychiatry. 2018 Sep;5(9):727-738. doi: 10.1016/S2215-0366(18)30269-4.The study systematically identified 133 double-blind randomized controlled trials (81 in children and adolescents, 51 in adults, and one in both) related to the efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. Summary odds ratios (ORs) and standardized mean differences (SMDs) were estimated using pairwise and network meta-analysis with random effects. For ADHD core symptoms rated by clinicians in children and adolescents, all included drugs were superior to placebo. By contrast, for comparisons based on teachers' ratings, only methylphenidate (SMD -0.82, 95% CI -1.16 to -0.48) and modafinil (-0.76, -1.15 to -0.37) were more efficacious than placebo. With respect to tolerability, amphetamines ([OR] 2.30, 95% CI 1.36-3.89) and guanfacine (2.64, 1.20-5.81) were inferior to placebo in both children and adolescents. Read MoreSafety and Side Effects of Rifampin versus Isoniazid in Children.Diallo T, Adjobimey M, Ruslami R, Trajman A, Sow O, Obeng Baah J, Marks GB, Long R, Elwood K, Zielinski D, Gninafon M, Wulandari DA, Apriani L, Valiquette C, Fregonese F, Hornby K, LiPZ, Hill PC, Schwartzman K, Benedetti A, Menzies DN Engl J Med. 2018 Aug 2;379(5):454-463. doi: 10.1056/NEJMoa1714284.The authors conducted a multicenter, open-label trial of 844 children (<18 years of age) with latent M. tuberculosis infection were randomized to receive 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events that resulted in the permanent discontinuation of a trial drug. There were no significant between-group differences in the rates of adverse events. The rates of safety and efficacy were similar in both groups, but treatment with 4 months of rifampin had better rates of adherence compared to 9 months of isoniazid. Read MoreRandomized controlled trials in pediatric patients had higher completion rates than adult trials: a cross-sectional study.Dufetelle E, 't Jong GW, KaguelidouJ Clin Epidemiol. 2018 Aug;100:53-60. doi: 10.1016/j.jclinepi.2018.04.018.This study aimed to evaluate the impact of the age of participants on completion rates of randomized controlled trials (RCTs), based on the RCTs registered at ClinicalTrials.gov up through December 31, 2016. Overall, pediatric and mixed age RCTs were more likely to be registered as completed than adult RCTs (odds ratio: 1.16, 95% CI: 1.02-1.30; odds ratio: 1.15, 95% CI: 1.04-1.27, respectively). Contrary to current perceptions and despite several specific challenges, recruitment of children and adolescents is not a limiting factor to completing a RCT. Read MoreSafety of repeated doses of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine in adults and adolescents.Jackson ML, Yu O, Nelson JC, Nordin JD, Tartof SY, Klein NP, Donahue JG, Irving SA, Glanz JM, McNeil MM, Jackson LAPharmacoepidemiol Drug Saf. 2018 Aug;27(8):921-925. doi: 10.1002/pds.4569.In the in the Vaccine Safety Datalink population, authors evaluated the safety of repeated doses of tetanus-containing vaccine in 68,915 nonpregnant adolescents and adults who had received an initial dose of Tdap. Compared to those who received a subsequent dose of Td vaccine, the those who received a subsequent dose of Tdap did not have significantly elevated risk of medical visits for seizure, cranial nerve disorders, limb swelling, pain in limb, cellulitis, paralytic syndromes, or encephalopathy/encephalitis/meningitis, suggesting that repeated Tdap vaccination has acceptable safety relative to Tdap vaccination followed by Td vaccination. Read MorePsychotropic Polypharmacy Among Children and Youth Receiving Medicaid, 2012-2015.Lohr WD, Creel L, Feygin Y, Stevenson M, Smith MJ, Myers J, Woods C, Liu G, Davis DWJ Manag Care Spec Pharm. 2018 Aug;24(8):736-744. doi: 10.18553/jmcp.2018.24.8.736.This study examined recent trends and determinants of interclass psychotropic polypharmacy (PP) use for 237,393 children and youth (age 0-17 years) with 1+ behavioral health diagnosis in the Kentucky Medicaid claims (2012-2015). Interclass PP was defined as 2+ psychotropic medication prescription fills for 2+ different classes of medication that, if taken as directed, would be used concurrently for at least 90 consecutive days. The primary 2-drug class combinations were stimulants with either alpha agonists or antidepressants. Children aged 6-11 years (beta = 3.08, 95% CI = 2.87, 3.29) and 12-17 years (beta = 1.61, 95% CI = 1.38, 1.83) had more covered months with PP compared with those aged 0-5 years. Read More Benzodiazepine (BZDs) prescribing for children, adolescents, and young adults from 2006 through 2013: A total population register-linkage study. Sidorchuk A, Isomura K, Molero Y, Hellner C, Lichtenstein P, Chang Z, Franck J, Fernández de la Cruz L, Mataix-Cols DPLoS Med. 2018 Aug 7;15(8):e1002635. doi: 10.1371/journal.pmed.1002635.The authors examined the prevalence rates, relative changes in rates over time, and prescribing patterns for BZD dispensation in 107,739 young people aged 0-24 years using the linkage of 3 nationwide Swedish health and administrative registers (2006-2013). Between 2006 and 2013, the prevalence rate of BZD dispensation among individuals aged 0-24 years increased by 22% from 0.81 per 100 inhabitants to 0.99 per 100 inhabitants. Nearly 30% of participants were prescribed a BZD for longer than 6 months (18% of children, 31% of adolescents, 31% of young adults). Age >11 years at the first BZD dispensation, lifetime psychiatric diagnosis or epilepsy, and concurrent use of other psychotropic drugs were associated with higher odds of being prescribed a BZD for longer than 6 months, high dose prescription, and heavy use. These findings highlight the need for close monitoring of prescribing practices for safe and efficient BZD treatment in young persons. Read More

Maternal pertussis vaccination has been introduced in several countries to protect infants from birth until routine infant vaccination takes place. This review assesses existing evidence on the effectiveness and safety of immunization in pregnancy. The evidence demonstrates efficient transplacental transfer of maternal antibodies in infants whose mothers were vaccinated with Tdap or Tdap/IPV in pregnancy, with good evidence that this protects against disease in young infants. Safety studies covering more than 150 000 women vaccinated mostly in the late second or third trimesters are generally consistent and provide reassurance of no significant increased risk of recognized maternal conditions or of adverse events (including congenital anomalies) in infants born to vaccinated women. Read More

This was a matched case-control study of pregnant women in Denmark who were born in Denmark between 1962 and 1994, and who were alive on their 18th birthday. The authors defined maternal mortality as deaths in pregnancy and the first 42 days after termination of pregnancy. The authors identified 2,105,084 pregnancies, including 11,976 (0.57%) pregnancies in which the mother was diagnosed with epilepsy. Of the 176 maternal deaths in this cohort, 5 women had a diagnosis of epilepsy. The mortality associated with an epilepsy diagnosis was >5 times higher compared to the mortality in women without this diagnosis (odds ratio 5.57, 95% confidence interval 2.23-13.9, p < 0.001). Read More

Keep it in the family: comparing perinatal risks in small-for-gestational-age infants based on population vs within-sibling designs.Cnattingius S, Kramer MS, Norman M, Ludvigsson JF, Fang F, Lu D.Int J Epidemiol. 2018 Sep 19. doi: 10.1093/ije/dyy196.The authors estimated perinatal risks of small-for-gestational-age (SGA) birth using both population-based and within-sibling analyses, where the latter by design controls for shared genetic factors and maternal environmental factors that are constant across pregnancies. The authors estimated associations between severe or moderate SGA (<3rd percentile and 3rd to <10th percentiles, respectively) and risks of stillbirth, neonatal mortality and morbidity, using both population-based and within-sibling analyses. Compared with non-SGA births (>10th percentile), the HR (95% CI) of stillbirth was 18.5 (95% CI 17.4-19.5) among severe SGA births in the population analysis and 22.5 (95% CI 18.7-27.1) in the within-sibling analysis. In non-malformed infants, RRs for neonatal mortality in moderate and severe SGA infants were similarly increased in both population and within-sibling analyses. Read More

Acetaminophen (paracetamol) exposure during pregnancy and pubertal development in boys and girls from a nationwide puberty cohort.Ernst A, Brix N, Lauridsen LLB, Olsen J, Parner ET, Liew Z, Olsen LH, Ramlau-Hansen CH.Am J Epidemiol.2018 Sep 7. doi: 10.1093/aje/kwy193.This study explored the association between exposure to acetaminophen during pregnancy and pubertal development using data from the longitudinal Puberty Cohort. Use of acetaminophen was reported three times during pregnancy and six months postpartum. Between 2012 and 2017, sons and daughters provided information on a wide range of pubertal milestones, including Tanner stages, axillary hair growth and age at menarche or voice break and first ejaculation, every six months from 11 years of age until full sexual maturation. The results suggested a tendency towards slightly earlier attainment of almost all studied markers of female pubertal development with increasing number of weeks of exposure. Male pubertal development had no strong association with acetaminophen exposure. Read More

This aim of the study was to follow the course of MDD in women with prior histories of depression followed during an index pregnancy. Out of 129 eligible women, 48.8% participated (N = 63) with an average/mean time of 12.9 years (SD = 1.9, 8.8-16.7) elapsed since participation in the prior pregnancy studies. Although approximately one third reported sustained remission from MDD since the pregnancy during which they had been originally followed, of the remaining two thirds of women who reported subsequent depressive episodes, almost one fifth (∼12% of the total sample) endorsed depression more than 50% of the time following their index pregnancy. Read More

Limited data are available on the safety of HepB administration during pregnancy. The authors examined a retrospective cohort of pregnancies in the Vaccine Safety Datalink (VSD). The authors compared pregnancies with HepB exposure to those with other vaccine exposures, and to those with no vaccine exposures. Among over 650,000 pregnancies in the study period, HepB was administered at a rate of 2.1 per 1000 pregnancies (n = 1399). There were no significant associations between HepB exposure during pregnancy and gestational hypertension, gestational diabetes, pre-eclampsia/eclampsia, cesarean delivery, pre-term delivery, low birthweight or small for gestational age infants. Read More

In a randomized, controlled, observer-blind, multicenter clinical trial, we measured the safety and immunogenicity of Tdap during pregnancy and the effect on the infant's immune response to primary vaccination at 2, 4, and 6 months and booster vaccination at 12 months of age. Rates of adverse events were similar in both groups. Infants of Tdap recipients had cord blood levels that were 21% higher than maternal levels for pertussis toxoid (PT), 13% higher for filamentous hemagglutinin (FHA), 4% higher for pertactin (PRN), and 7% higher for fimbriae (FIM). These infants had significantly higher PT antibody levels at birth and at 2 months and significantly higher FHA, PRN, and FIM antibodies at birth and 2 and 4 months, but significantly lower PT and FHA antibody levels at 6 and 7 months and significantly lower PRN and FIM antibody levels at 7 months than infants whose mothers received Td. Read More

Maternal use of hormonal contraception and risk of childhood leukaemia: a nationwide, population-based cohort study.Hargreave M, Mørch LS, Andersen KK, Winther JF, Schmiegelow K, Kjaer SK.Lancet Oncol.2018 Oct;19:1307-1314. doi: 10.1016/S1470-2045(18)30479-0.The aim of this study was to assess the association between maternal use of hormonal contraception and diagnosis of leukaemia in their children. Children born to women with recent use of any type of hormonal contraception were at higher risk for any leukaemia than children of women who never used contraception (HR 1·46, 95% CI 1·09-1·96; p=0·011); and for exposure during pregnancy the risk was 1·78 (0·95-3·31; p=0·070). No association was found between timing of use and risk for lymphoid leukaemia (HR 1·23, 95% CI 0·97-1·57, p=0·089, for previous use and 1·27, 0·90-1·80, p=0·167, for recent use); however, the HRs for non-lymphoid leukaemia were 2·17 (1·22-3·87; p=0·008) for recent use and 3·87 (1·48-10·15; p=0·006) for use during pregnancy. Read More

Congenital anomaly registries have two main surveillance aims: firstly to define baseline epidemiology of important congenital anomalies to facilitate programme, policy and resource planning, and secondly to identify clusters of cases and any other epidemiological changes that could give early warning of environmental or infectious hazards. However, setting up a sustainable registry and surveillance system is resource-intensive requiring national infrastructure for recording all cases and diagnostic facilities to identify those malformations that that are not externally visible. The authors describe how registry data from high-income settings can be used for generating reference rates that can be used as provisional estimates for countries with little or no observational data on non-syndromic congenital malformations. Read More

Due to the ethical dilemma in carrying out experimental drug studies on pregnant women, the effects of medication usage during pregnancy on fetal and maternal outcomes are largely evaluated using electronic health data. One major limitation in this type of study is the delayed inclusion of pregnancies in the cohort. The purpose of this study was to demonstrate three methods that can be used to assess the extent of selection bias due to the delayed inclusion of pregnancies. The authors use causal directed acyclic graphs to explain the source of this selection bias. The authors find that this selection bias can be partially mitigated by controlling for variables related to (spontaneous or therapeutic) abortion and the outcome of interest. The three proposed methods allow for the pre and post hoc ascertainment of the bias. Read More

Predicting attention deficit hyperactivity disorder using pregnancy and birth characteristics.Arch Gynecol Obstet. 2018 Nov;298:889-895. doi: 10.1007/s00404-018-4888-0.Schwenke E, Fasching PA, Faschingbauer F, Pretscher J, Kehl S, Peretz R, Keller A, Häberle L, Eichler A, Irlbauer-Müller V, Dammer U, Beckmann MW, Schneider M.The aim of this study was to evaluate maternal, prenatal, perinatal, and postpartum parameters as risk factors for the later development of an attention deficit hyperactivity disorder (ADHD) in the child. A total of 573 mother and child pairs were analyzed. Forty-four of the mothers reported that their child had ADHD (7.7%). No significant associations were found for the following parameters: mother's age; mother's educational level; number of the pregnancy; maternal weight before and at the end of pregnancy; mother's height; alcohol consumption during pregnancy; mode of delivery; gestational week; birthweight; umbilical artery blood values; Apgar score at 5 and 10 min; or breastfeeding. The parameters of smoking in pregnancy and an Apgar score lower than 7 after 1 min were significantly associated with a risk for later development of ADHD. Read More

Low-molecular-weight heparin for the prevention and treatment of placenta-mediated pregnancy complications: The tides have shifted.Skeith L.Thromb Res.2018 Oct;170:207-208. doi: 10.1016/j.thromres.2018.09.045.

What is the role of low-molecular-weight heparin (LMWH) in the prevention and treatment of placenta-mediated pregnancy complications? Intrauterine growth restriction (IUGR), pre-eclampsia, placental abruption and late pregnancy loss are placenta-mediated complications associated with important morbidity and mortality. Based on the available high-quality evidence, there is currently no role for LMWH for the prevention of recurrent placenta-mediated pregnancy complications outside of a clinical trial. Recruitment and funding of clinical trials in pregnancy is challenging but are needed to guide practice. While many studies have a small sample size that limits definitive conclusions, international collaboration and pooling of patient data from well-conducted randomized trials has helped move this important field forward to improve patient care. Read More

Aim and design of pREGnant, the Dutch Pregnancy Drug Register.Vorstenbosch S, Te Winkel B, van Gelder MMHJ, Kant A, Roeleveld N, van Puijenbroek E.Drug Saf.2018 Sep 24. doi: 10.1007/s40264-018-0722-7. ​The pREGnant, the Dutch Pregnancy Drug Register, was set up to obtain insight into medication use among pregnant and breastfeeding women and potential effects on maternal and fetal/infant health. The register has a prospective cohort design. Data collection started in April 2014 and enrollment of women is continuous and is characterized by a relative high proportion of women born in the Netherlands with a high education compared with the general Dutch pregnant population. Data on current pregnancy, obstetric history, maternal lifestyle, health and medication use, delivery, and infant health are collected through web-based questionnaires completed by the participating women (three times during pregnancy and three times during the infant's first year of life). Read More

Use of existing electronic health care databases to evaluate medication safety in pregnancy: triptan exposure in pregnancy as a case study.Yusuf A, Chia V, Xue F, Mikol DD, Bollinger L, Cangialose C.Pharmacoepidemiol Drug Saf.2018 Sep 21. doi: 10.1002/pds.4658. ​The recent expansion of electronic health and medical record systems may present an opportunity to generate robust post-approval safety data and obviate the limitations of prospective pregnancy exposure registries. The authors examined and compared, over the same time frame, the outcomes of triptan exposure in pregnancy using a retrospective claims database and a previously completed pregnancy registry. The proportion of major birth defects among first-semester sumatriptan exposures was 4.0%, which is exactly the same as the proportion of major birth defects reported for first-semester sumatriptan exposures in the registry. There were very few non-livebirth outcomes in both the claims analyses and registry. Read More

Pediatrics ​

​Prescription medication use among children and adolescents in the United States.Qato DM, Alexander GC, Guadamuz JS, Lindau STPediatrics. 2018 Sep;142(3). pii: e20181042. doi: 10.1542/peds.2018-1042.The authors estimate the prevalence of prescription medication use, concurrent use (use of ≥2 prescription medications), and potential major drug-drug interactions (DDIs) in US children and adolescents (age <19 years) using data from NHANES. During 2013-2014, 19.8% of children and adolescents used at least 1 prescription medication. Concurrent use of prescription medications was 7.5% overall and was highest among boys 6 to 12 years old (12%). 8.2% of concurrent users of prescription medications were at risk for a potentially major DDI, with a vast majority of DDI regimens involving antidepressants. Read MoreLabeling changes and costs for clinical trials performed under the US Food and Drug Administration pediatric exclusivity extension, 2007 to 2012.Sinha MS, Najafzadeh M, Rajasingh EK, Love J, Kesselheim ASJAMA Intern Med. 2018 Sep 24. doi: 10.1001/jamainternmed.2018.3933. [Epub ahead of print]The objective of this study was to review updates to drug labeling and the cost to consumers of extending market exclusivity related to the pediatric exclusivity program. Label changes were evaluated for 54 drugs that earned pediatric exclusivity incentive between 2007-2012. One hundred forty one trials were identified, which led to 29 extended indications, 3 new indications, and new safety information for 16 drugs. Median cost of investment for trials was $36.4 million (IQR, $16.6 to $100.6 million). Median net return was $176.0 million (IQR, $47.0 million to $404.1 million), with a median ratio of net return to cost of investment of 680% (IQR, 80% to 1270%). The costs to consumers have been high, exceeding the estimated costs of investment for conducting the trials. Read MoreGlucocorticoids and the risk of schizophrenia spectrum disorder in childhood and adolescence - a Danish nationwide study.C Broberg BV, Sommer IE, Benros ME, Glenthøj BY, Gasse C, Köhler-Forsberg O Schizophr Res. 2018 Sep;199: doi: 10.1016/j.schres.2018.03.007The authors conducted the first large-scale longitudinal study examining the association between glucocorticoid treatment and development of psychosis using data on all children and adolescents born in Denmark 1995-2003 (n=597,257). Cox regression was used to estimate hazard rate ratios (HRR). The risk for a subsequent diagnosis of early-onset schizophrenia spectrum disorder (N=1141) was increased after exposure to both non-systemic (HRR=1.47; 95%-CI=1.25-1.73; N=371) and systemic glucocorticoids (HRR=1.66; 95%-CI=1.13-2.43; N=34), when compared to non-exposed individuals, with similar findings when using an active comparator group. However, in individuals with asthma, exposure to glucocorticoids did not further increase the risk of psychosis. Read MoreDetecting the diverted use of psychoactive drugs by adolescents and young adults: a pilot study.Jouanjus E, Falcou A, Deheul S, Roussin A, Lapeyre-Mestre MPharmacoepidemiol Drug Saf. 2018 Sep 25. doi: 10.1002/pds.4624.This study implemented this pilot study before a national investigation to identify requests for suspected recreational use of psychoactive drugs made by young subjects to community pharmacies. Between December 12, 2016 to January 23, 2017, 38 French community pharmacies were asked to complete questionnaire for each suspect request formulated by subjects <26 years old, from which 19 pharmacies participated. Forty-one requests mentioning 51 drugs were reported, mostly concerning males (85%). The most frequent age class was that comprised between 18 and 20 years old. Codeine and promethazine, the main components of the popular cocktail Purple drank, were the most requested. Read MoreA longitudinal healthcare use profile of children with a history of neonatal abstinence syndrome.Liu G, Kong L, Leslie DL, Corr TEJ Pediatr. 2018 Sep 27. pii: S0022-3476(18)31157-0. doi: 10.1016/j.jpeds.2018.08.032. The objective of this study was to describe healthcare use over time of children with a history of neonatal abstinence syndrome (NAS) compared with children without NAS. Children in the MarketScan databases (2005-2014) were followed until 8 years or disenrollment (mean: 35 months). Children with NAS had a significantly greater number of claims per year from age 1 to 8 for inpatient hospitalizations (adjusted mean ratio 3.20; 95% CI 1.74-5.90), outpatient encounters (1.23; 1.08-1.41), and emergency department visits (1.46; 1.25-1.70) adjustment for confounders. Adjusted mean annualized costs were nearly double for all healthcare services in children with NAS (1.86; 1.34-2.60) and >4 times as high as for inpatient hospitalizations (4.34; 2.03-9.30) compared with children without NAS. Read MoreThe association between early life antibiotic use and allergic disease in young children: recent insights and their implications.Obiakor CV, Tun HM, Bridgman SL, Arrieta MC, Kozyrskyj ALExpert Rev Clin Immunol. 2018 Oct;14(10):841-855. doi: 10.1080/1744666X.2018.1521271. Authors conducted a meta-analysis of prospective or databases cohorts that examined the link between infant antibiotic treatment and the development of atopy. To date, the stronger associations seen with multiple course and broad-spectrum antibiotic treatment add to biological plausibility, but large-scale profiling of the gut microbiome now provides a new tool for disentangling potential biases found in these observational studies. Continued study of the infant gut microbiome, mycobiome, or resistome will provide a closer link to antibiotic treatment or refute it as a cause of allergic disease. Read More

Choice of time period to identify confounders for propensity score matching, affected the estimate: a retrospective cohort study of drug effectiveness in asthmatic children.Osokogu OU, Khan J, Nakato S, Weibel D, de Ridder M, Sturkenboom MCJM, Verhamme KJ Clin Epidemiol. 2018 Sep;101:107-115.e3. doi: 10.1016/j.jclinepi.2018.01.008This study compared the effect of using different look-back periods in electronic health-care data to construct propensity scores (PSs), with an application in the effect of a combination of inhaled corticosteroids/long-acting beta-2 agonists (ICS + LABA) in the prevention of severe asthma exacerbations. Authors identified new users of ICS + LABA, either as fixed combination or loose combination, in a cohort of children (5-17 years) diagnosed with asthma from the Dutch Integrated Primary Care information database. PSs were estimated using different time windows: 1 week, 1 month, 3 months, 1 year, and full history prior to the start of treatment. PS matching was used control for confounding. Controlling for confounders occurring in the 3 months preceding drug exposure resulted in the largest adjustment of the crude HR and yielded results comparable to clinical trial results. Read MoreComparative effectiveness of surgical treatments for pediatric hydrocephalus.Pan IW, Harris DA, Luerssen TG, Lam SKNeurosurgery. 2018 Sep 1;83(3):480-487. doi: 10.1093/neuros/nyx440.This study performed a comparative effectiveness analysis for endoscopic third ventriculostomy (ETV) and cerebrospinal fluid shunt placement in pediatric hydrocephalus patients (age <19 years) in the US using the MarketScan database (2003-2011) through the application of propensity scores matching. Among discordant pairs, ETV patients were more likely to experience surgery failure compared to patients receiving shunt (relative risk = 1.4, P value = .011). Furthermore, patients' age < 1 year had lower ETV success rates than those with shunt (P value = .009). Read More